US20220104493A1 - Herbicidal compounds - Google Patents

Herbicidal compounds Download PDF

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US20220104493A1
US20220104493A1 US17/428,433 US202017428433A US2022104493A1 US 20220104493 A1 US20220104493 A1 US 20220104493A1 US 202017428433 A US202017428433 A US 202017428433A US 2022104493 A1 US2022104493 A1 US 2022104493A1
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group
alkyl
formula
hydrogen
phenyl
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James Nicholas Scutt
Nigel James Willetts
John Stephen Delaney
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Syngenta Crop Protection AG Switzerland
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Syngenta Crop Protection AG Switzerland
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Assigned to SYNGENTA CROP PROTECTION AG reassignment SYNGENTA CROP PROTECTION AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DELANEY, JOHN STEPHEN, SCUTT, JAMES NICHOLAS, WILLETTS, NIGEL JAMES
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N57/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds
    • A01N57/18—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-carbon bonds
    • A01N57/20—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-carbon bonds containing acyclic or cycloaliphatic radicals
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
    • A01N43/647—Triazoles; Hydrogenated triazoles
    • A01N43/653—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/713—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with four or more nitrogen atoms as the only ring hetero atoms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • A01N43/76—1,3-Oxazoles; Hydrogenated 1,3-oxazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P13/00—Herbicides; Algicides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to herbicidally active pyridinium derivatives, as well as to processes and intermediates used for the preparation of such derivatives.
  • the invention further extends to herbicidal compositions comprising such derivatives, as well as to the use of such compounds and compositions for controlling undesirable plant growth: in particular the use for controlling weeds, in crops of useful plants.
  • the present invention is based on the finding that pyridinium derivatives of formula (I) as defined herein, exhibit surprisingly good herbicidal activity.
  • R 1 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, —OR 7 , —OR 15a , —N(R 6 )S(O) 2 R 15 , —N(R 6 )C(O)R 15 , —N(R 6 )C(O)OR 15 , —N(R 6 )C(O)NR 16 R 17 , —N(R 6 )CHO, —N(R 7a ) 2 and —S(O) r R 15 ;
  • R 2 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl; and wherein when R 1 is selected from the group consisting of —OR 7 , —OR 15a
  • Q is (CR 1a R 2b ) m ;
  • each R 1a and R 2b are independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OH, —OR 7 , —OR 15a , —NH 2 , —NHR 7 , —NHR 15a , —N(R 6 )CHO, —NR 7b R 7c and —S(O) r R 15 ; or each R 1a and R 2b together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl ring or a 3- to 6-membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O; and R 3 , R 3a , R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, —S(O) r R 15 , C 1 -C 6 alkyl, C 1 -C 6
  • an agrochemical composition comprising a herbicidally effective amount of a compound of formula (I) and an agrochemically-acceptable diluent or carrier.
  • Such an agricultural composition may further comprise at least one additional active ingredient.
  • a method of controlling or preventing undesirable plant growth wherein a herbicidally effective amount of a compound of formula (I), or a composition comprising this compound as active ingredient, is applied to the plants, to parts thereof or the locus thereof.
  • halogen refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo), preferably fluorine, chlorine or bromine.
  • cyano means a —CN group.
  • hydroxy means an —OH group.
  • nitro means an —NO 2 group.
  • C 1 -C 6 alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • C 1 -C 4 alkyl and C 1 -C 2 alkyl are to be construed accordingly.
  • Examples of C 1 -C 6 alkyl include, but are not limited to, methyl (Me), ethyl (Et), n-propyl, 1-methylethyl (iso-propyl), n-butyl, and 1-dimethylethyl (t-butyl).
  • C 1 -C 6 alkoxy refers to a radical of the formula —OR a where R a is a C 1 -C 6 alkyl radical as generally defined above.
  • C 1 -C 4 alkoxy is to be construed accordingly.
  • Examples of C 1-4 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy and t-butoxy.
  • C 1 -C 6 haloalkyl refers to a C 1 -C 6 alkyl radical as generally defined above substituted by one or more of the same or different halogen atoms.
  • C 1 -C 4 haloalkyl is to be construed accordingly.
  • Examples of C 1 -C 6 haloalkyl include, but are not limited to chloromethyl, fluoromethyl, fluoroethyl, difluoromethyl, trifluoromethyl and 2,2,2-trifluoroethyl.
  • C 2 -C 6 alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond that can be of either the (E)- or (Z)-configuration, having from two to six carbon atoms, which is attached to the rest of the molecule by a single bond.
  • C 2 -C 4 alkenyl is to be construed accordingly.
  • Examples of C 2 -C 6 alkenyl include, but are not limited to, prop-1-enyl, allyl (prop-2-enyl) and but-1-enyl.
  • C 2 -C 6 haloalkenyl refers to a C 2 -C 6 alkenyl radical as generally defined above substituted by one or more of the same or different halogen atoms.
  • Examples of C 2 -C 6 haloalkenyl include, but are not limited to chloroethylene, fluoroethylene, 1,1-difluoroethylene, 1,1-dichloroethylene and 1,1,2-trichloroethylene.
  • C 2 -C 6 alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to six carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • C 2 -C 4 alkynyl is to be construed accordingly.
  • Examples of C 2 -C 6 alkynyl include, but are not limited to, prop-1-ynyl, propargyl (prop-2-ynyl) and but-1-ynyl.
  • C 1 -C 6 haloalkoxy refers to a C 1 -C 6 alkoxy group as defined above substituted by one or more of the same or different halogen atoms.
  • C 1 -C 4 haloalkoxy is to be construed accordingly.
  • Examples of C 1 -C 5 haloalkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, fluoroethoxy, trifluoromethoxy and trifluoroethoxy.
  • C 1 -C 3 haloalkoxyC 1 -C 3 alkyl refers to a radical of the formula R b —O—R a — where R b is a C 1 -C 3 haloalkyl radical as generally defined above, and R a is a C 1 -C 3 alkylene radical as generally defined above.
  • C 1 -C 3 alkoxyC 1 -C 3 alkyl refers to a radical of the formula R b —O—R a — where R b is a C 1 -C 3 alkyl radical as generally defined above, and R a is a C 1 -C 3 alkylene radical as generally defined above.
  • C 1 -C 3 alkoxyC 1 -C 3 alkoxy- refers to a radical of the formula R b —O—R a —O— where R b is a C 1 -C 3 alkyl radical as generally defined above, and R a is a C 1 -C 3 alkylene radical as generally defined above.
  • C 3 -C 6 alkenyloxy refers to a radical of the formula —OR a where R a is a C 3 -C 6 alkenyl radical as generally defined above.
  • C 3 -C 6 alkynyloxy refers to a radical of the formula —OR a where R a is a C 3 -C 6 alkynyl radical as generally defined above.
  • hydroxyC 1 -C 6 alkyl refers to a C 1 -C 6 alkyl radical as generally defined above substituted by one or more hydroxy groups.
  • C 1 -C 6 alkylcarbonyl refers to a radical of the formula —C(O)R a where R a is a C 1 -C 6 alkyl radical as generally defined above.
  • C 1 -C 6 alkoxycarbonyl refers to a radical of the formula —C(O)OR a where R a is a C 1 -C 6 alkyl radical as generally defined above.
  • aminocarbonyl refers to a radical of the formula —C(O)NH 2 .
  • C 3 -C 6 cycloalkyl refers to a stable, monocyclic ring radical which is saturated or partially unsaturated and contains 3 to 6 carbon atoms.
  • C 3 -C 4 cycloalkyl is to be construed accordingly.
  • Examples of C 3 -C 6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • C 3 -C 6 halocycloalkyl refers to a C 3 -C 6 cycloalkyl radical as generally defined above substituted by one or more of the same or different halogen atoms.
  • C 3 -C 4 halocycloalkyl is to be construed accordingly.
  • C 3 -C 6 cycloalkoxy refers to a radical of the formula —OR a where R a is a C 3 -C 6 cycloalkyl radical as generally defined above.
  • N—C 3 -C 6 cycloalkylamino refers to a radical of the formula —NHR a where R a is a C 3 -C 6 cycloalkyl radical as generally defined above.
  • heteroaryl refers to a 5- or 6-membered monocyclic aromatic ring which comprises 1, 2, 3 or 4 heteroatoms individually selected from nitrogen, oxygen and sulfur.
  • the heteroaryl radical may be bonded to the rest of the molecule via a carbon atom or heteroatom.
  • heteroaryl include, furyl, pyrrolyl, imidazolyl, thienyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidyl or pyridyl.
  • heterocyclyl refers to a stable 4- to 6-membered non-aromatic monocyclic ring radical which comprises 1, 2, or 3 heteroatoms individually selected from nitrogen, oxygen and sulfur.
  • the heterocyclyl radical may be bonded to the rest of the molecule via a carbon atom or heteroatom.
  • heterocyclyl examples include, but are not limited to, pyrrolinyl, pyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydrothiopyranyl, piperidyl, piperazinyl, tetrahydropyranyl, dihydroisoxazolyl, dioxolanyl, morpholinyl or ⁇ -lactamyl.
  • formula (I) is intended to include all those possible isomeric forms and mixtures thereof.
  • the present invention includes all those possible isomeric forms and mixtures thereof for a compound of formula (I).
  • formula (I) is intended to include all possible tautomers (including lactam-lactim tautomerism and keto-enol tautomerism) where present.
  • the present invention includes all possible tautomeric forms for a compound of formula (I).
  • di-substituted alkenes these may be present in E or Z form or as mixtures of both in any proportion.
  • the present invention includes all these possible isomeric forms and mixtures thereof for a compound of formula (I).
  • the compounds of formula (I) will typically be provided in the form of an agronomically acceptable salt, a zwitterion or an agronomically acceptable salt of a zwitterion.
  • This invention covers all such agronomically acceptable salts, zwitterions and mixtures thereof in all proportions.
  • a compound of formula (I) wherein Z comprises an acidic proton may exist as a zwitterion, a compound of formula (I-I), or as an agronomically acceptable salt, a compound of formula (I-II) as shown below:
  • Y represents an agronomically acceptable anion and j and k represent integers that may be selected from 1, 2 or 3, dependent upon the charge of the respective anion Y.
  • a compound of formula (I) may also exist as an agronomically acceptable salt of a zwitterion, a compound of formula (I-Ill) as shown below:
  • Y represents an agronomically acceptable anion
  • M represents an agronomically acceptable cation (in addition to the pyridinium cation) and the integers j, k and q may be selected from 1, 2 or 3, dependent upon the charge of the respective anion Y and respective cation M.
  • a compound of formula (I-II) wherein k is 2, j is 1 and Y is selected from the group consisting of halogen, trifluoroacetate and pentafluoropropionate.
  • a nitrogen atom in the ring A may be protonated or a nitrogen atom comprised in R 1 , R 2 , Q or X may be protonated.
  • k is 2, j is 1 and Y is chloride, wherein a nitrogen atom in the ring comprising A is protonated.
  • Suitable agronomically acceptable salts of the present invention include but are not limited chloride, bromide, iodide, fluoride, 2-naphthalenesulfonate, acetate, adipate, methoxide, ethoxide, propoxide, butoxide, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, butylsulfate, butylsulfonate, butyrate, camphorate, camsylate, caprate, caproate, caprylate, carbonate, citrate, diphosphate, edetate, edisylate, enanthate, ethanedisulfonate, ethanesulfonate, ethylsulfate, formate, fumarate, gluceptate, gluconate, glucoronate, glutamate, glycerophosphate, hepta
  • Suitable cations represented by M include, but are not limited to, metals, conjugate acids of amines and organic cations.
  • suitable metals include aluminium, calcium, cesium, copper, lithium, magnesium, manganese, potassium, sodium, iron and zinc.
  • Suitable amines include allylamine, ammonia, amylamine, arginine, benethamine, benzathine, butenyl-2-amine, butylamine, butylethanolamine, cyclohexylamine, decylamine, diamylamine, dibutylamine, diethanolamine, diethylamine, diethylenetriamine, diheptylamine, dihexylamine, diisoamylamine, diisopropylamine, dimethylamine, dioctylamine, dipropanolamine, dipropargylamine, dipropylamine, dodecylamine, ethanolamine, ethylamine, ethylbutylamine, ethylenediamine, ethylheptylamine, ethyloctylamine, ethylpropanolamine, heptadecylamine, heptylamine, hexadecylamine, he
  • Suitable organic cations include benzyltributylammonium, benzyltrimethylammonium, benzyltriphenylphosphonium, choline, tetrabutylammonium, tetrabutylphosphonium, tetraethylammonium, tetraethylphosphonium, tetramethylammonium, tetramethylphosphonium, tetrapropylammonium, tetrapropylphosphonium, tributylsulfonium, tributylsulfoxonium, triethylsulfonium, triethylsulfoxonium, trimethylsulfonium, trimethylsulfoxonium, tripropylsulfonium and tripropylsulfoxonium.
  • Preferred compounds of formula (I), wherein Z comprises an acidic proton can be represented as either (I-I) or (I-II).
  • Y is chloride, bromide, iodide, hydroxide, bicarbonate, acetate, trifluoroacetate, methylsulfate, tosylate and nitrate, wherein j and k are 1.
  • R 1 , R 2 , R 3 , R 3a , R 4 , R 5 , A and Z are as defined for compounds of formula (I).
  • R 1 , R 2 , R 1a , R 2b , R 3 , R 3a , R 4 , R 5 , A and Z are as defined for compounds of formula (I).
  • R 1 , R 2 , R 1a , R 2b , R 3 , R 3a , R 4 , R 5 , A and Z are as defined for compounds of formula (I).
  • R 1 , R 2 , R 1a , R 2b , R 3 , R 3a , R 4 , R 5 , A and Z are as defined for compounds of formula (I).
  • R 1 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, —OR 7 , —OR 15a , —N(R 6 )S(O) 2 R 15 , —N(R 6 )C(O)R 15 , —N(R 6 )C(O)OR 15 , —N(R 6 )C(O)NR 16 R 17 , —N(R 6 )CHO, —N(R 7a ) 2 and —S(O) r R 15 .
  • R 1 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, —OR 7 , —NHS(O) 2 R 15 , —NHC(O)R 15 , —NHC(O)OR 15 , —NHC(O)NR 16 R 17 , —N(R 7a ) 2 and —S(O) r R 15 . More preferably, R 1 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, —OR 7 and —N(R 7a ) 2 .
  • R 1 is selected from the group consisting of hydrogen, halogen and C 1 -C 6 alkyl. Even more preferably still, R 1 is hydrogen or C 1 -C 6 alkyl. Yet even more preferably still, R 1 is hydrogen or methyl. Most preferably R 1 is hydrogen.
  • R 2 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl.
  • R 2 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl and C 1 -C 6 fluoroalkyl. More preferably, R 2 is hydrogen or C 1 -C 6 alkyl. Even more preferably, R 2 is hydrogen or methyl. Most preferably R 2 is hydrogen.
  • R 1 is selected from the group consisting of —OR 7 , —OR 15a , —N(R 6 )S(O) 2 R 15 , —N(R 6 )C(O)R 15 , —N(R 6 )C(O)OR 15 , —N(R 6 )C(O)NR 16 R 17 , —N(R 6 )CHO, —N(R 7a ) 2 and —S(O) r R 15
  • R 2 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl.
  • R 1 is selected from the group consisting of —OR 7 , —NHS(O) 2 R 15 , —NHC(O)R 15 , —NHC(O)OR 15 , —NHC(O)NR 16 R 17 , —N(R 7a ) 2 and —S(O) r R 15
  • R 2 is selected from the group consisting of hydrogen and methyl.
  • R 1 and R 2 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl ring or a 3- to 6-membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O.
  • R 1 and R 2 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl ring.
  • R 1 and R 2 together with the carbon atom to which they are attached form a cyclopropyl ring.
  • R 1 and R 2 are hydrogen.
  • R 1 is methyl and R 2 is hydrogen.
  • R 1 is methyl and R 2 is methyl.
  • Q is (CR 1a R 2b ) m .
  • m is 0, 1, 2 or 3.
  • m is 0, 1 or 2. More preferably, m is 0 or 1. Most preferably, m is 0.
  • Each R 1a and R 2b are independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OH, —OR 7 , —OR 15a , —NH 2 , —NHR 7 , —NHR 15a , —N(R 6 )CHO, —NR 7b R 7c and —S(O) r R 15 .
  • each R 1a and R 2b are independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, —OH, —NH 2 and —NHR 7 .
  • each Ria and R 2b are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, —OH and —NH 2 . Even more preferably, each R 1a and R 2b are independently selected from the group consisting of hydrogen, methyl, —OH and —NH 2 . Even more preferably still, each R 1a and R 2b are independently selected from the group consisting of hydrogen and methyl. Most preferably R 1a and R 2b are hydrogen.
  • each R 1a and R 2b are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl.
  • each R 1a and R 2b together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl ring or a 3- to 6-membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O.
  • each R 1a and R 2b together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl ring.
  • each R 1a and R 2b together with the carbon atom to which they are attached form a cyclopropyl ring.
  • R 3 , R 3a , R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, —S(O) r R 15 , C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 fluoroalkoxy, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl and —N(R 6 ) 2 .
  • R 3 , R 3a , R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 fluoroalkoxy, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl and —N(R 6 ) 2 . More preferably, R 3 , R 3a , R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl and C 1 -C 6 fluoroalkyl.
  • R 3 , R 3a , R 4 and R 5 are independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, cyano, methyl and trifluoromethyl. Even more preferably still, R 3 , R 3a , R 4 and R 5 are independently selected from the group consisting of hydrogen, chloro, fluoro, bromo and methyl. Yet even more preferably still, R 3 , R 3a , R 4 and R 5 are independently selected from the group consisting of hydrogen, chloro and fluoro. Most preferably, R 3 , R 3a , R 4 and R 5 are hydrogen.
  • R 3 and R 3a are hydrogen, and R 4 and R 5 are independently selected from the group consisting of hydrogen, bromo, chloro, fluoro and —S(O) 2 Me (preferably, hydrogen, chloro and fluoro).
  • Each R 6 is independently selected from hydrogen and C 1 -C 6 alkyl. Preferably, each R 6 is independently selected from hydrogen and methyl.
  • Each R 7 is independently selected from the group consisting of C 1 -C 6 alkyl, —S(O) 2 R 15 , —C(O)R 15 , —C(O)OR 15 and —C(O)NR 16 R 17 .
  • each R 7 is independently selected from the group consisting of C 1 -C 6 alkyl, —C(O)R 15 and —C(O)NR 16 R 17 . More preferably, each R 7 is C 1 -C 6 alkyl. Most preferably, each R 7 is methyl.
  • Each R 7a is independently selected from the group consisting of —S(O) 2 R 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)NR 16 R 17 and —C(O)NR 6 R 15a .
  • each R 7a is independently —C(O)R 15 or —C(O)NR 16 R 17 .
  • R 7b and R 7c are independently selected from the group consisting of C 1 -C 6 alkyl, —S(O) 2 R 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)NR 16 R 17 and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R 9 substituents, which may be the same or different.
  • R 7b and R 7c are independently selected from the group consisting of C 1 -C 6 alkyl, —C(O)R 15 and —C(O)NR 16 R 17 . More preferably, R 7b and R 7c are C 1 -C 6 alkyl. Most preferably, R 7b and R 7c are methyl.
  • R 7b and R 7c together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S.
  • R 7b and R 7c together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N and O.
  • R 7b and R 7c together with the nitrogen atom to which they are attached form an pyrrolidyl, oxazolidinyl, imidazolidinyl, piperidyl, piperazinyl or morpholinyl group.
  • A is a 5-membered heteroaryl attached to the rest of the molecule via a ring carbon atom, which comprises 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S, and wherein the heteroaryl may, where feasible, be optionally substituted by 1, 2 or 3 R 8 substituents, which may be the same or different.
  • A is a heteroaryl selected from the group consisting of 1,2,4-oxadiazol-5-yl, thiadiazol-5-yl, 1,2,4-thiadiazol-5-yl, thiadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,5-thiadiazol-3-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,5-oxadiazol-3-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, triazol-4-yl, triazol-5-yl, 2-methyltetrazol-5-yl, 1-methyltetrazol-5-yl, thiazol-2-yl, thiazol-4-yl, isothiazol-5-yl, isothiazol-4-yl, isothiazol-3-yl, oxazol-2-yl
  • A is selected from the group consisting of formula A-I to A-XXXV below
  • R 8a , R 8b , R 8c , R 8d , R 10 , R 15 , R 16 , R 17 and r are as defined herein.
  • R 8a , R 8b , R 8c , R 8d are examples of R 8 wherein the subscript letter a, b, c and d are used to denote positions within individual heterocycles (A-I to A-XXXV).
  • A is selected from the group consisting of formula A-I to A-XXXII below
  • A is selected from the group consisting of formula A-1 to A-X, A-XVII, A-XVIII, A-XIX, A-XXIII, A-XXIV and AXXVII below
  • A is selected from the group consisting of formula A-I to A-III below
  • A is selected from the group consisting of formula A-Ia to A-Xa below
  • A is selected from the group consisting of formula A-Ia to A-XXXXVIIa below
  • each R 8 is independently selected from the group consisting of halogen, nitro, cyano, —NH 2 , —NHR 7 , —N(R 7 ) 2 , —OH, —OR 7 , —S(O) r R 15 , —NR 6 S(O) 2 R 15 , —C(O)OR 10 , —C(O)R 15 , —C(O)NR 16 R 17 , —S(O) 2 NR 16 R 17 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, C 3 -C 6 cycloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 1 -C 3 alkoxyC
  • each R 8 is independently selected from the group consisting of halogen, nitro, cyano, —NH 2 , —NHR 7 , —N(R 7 ) 2 , —OH, —OR 7 , —S(O) r R 15 , —NR 6 S(O) 2 R 15 , —C(O)OR 10 , —C(O)R 15 , —C(O)NR 16 R 17 , —S(O) 2 NR 16 R 17 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, C 3 -C 6 cycloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 1 -C 3
  • each R 8 is independently selected from the group consisting of halogen, nitro, cyano, —NH 2 , —NHR 7 , —N(R 7 ) 2 , —OH, —OR 7 , —S(O) r R 15 , —NR 6 S(O) 2 R 15 , —C(O)OR 10 , —C(O)R 15 , —C(O)NR 16 R 17 , —S(O) 2 NR 16 R 17 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxyC 1 -C 3 alkyl-, hydroxyC 1 -C 6 alkyl-, C 1 -C 3 alkoxyC 1 -C 3 alkoxy- and C 1 -C 6 haloalkoxy.
  • each R 8 is independently selected from the group consisting of halogen, nitro, cyano, —NH 2 , —OH, —S(O) r R 15 , —C(O)OR 10 , —C(O)R 15 , —C(O)NR 16 R 17 , —S(O) 2 NR 16 R 17 , C 1 -C 6 alkyl and C 1 -C 6 haloalkyl.
  • each R 8 is independently selected from the group consisting of halogen, cyano, —NH 2 , —OH, —C(O)NR 16 R 17 , C 1 -C 6 alkyl and C 1 -C 6 haloalkyl.
  • each R 8 is independently selected from the group consisting of halogen, cyano, —NH 2 , —C(O)NR 16 R 17 , C 1 -C 6 alkyl and C 1 -C 6 haloalkyl.
  • each R 8 is independently selected from the group consisting of bromo, chloro, fluoro, cyano, —NH 2 , —C(O)NH 2 , —C(O)NHMe, —C(O)N(Me) 2 , methyl and trifluoromethyl.
  • each R 8 is independently selected from the group consisting of bromo, —NH 2 , —C(O)NHMe, methyl and trifluoromethyl.
  • each R 8 is independently selected from the group consisting of bromo, cyano, —NH 2 , —C(O)NHMe, methyl, trifluoromethyl and phenyl (preferably, each R 8 is independently selected from the group consisting of —C(O)NHMe, methyl and trifluoromethyl).
  • R 8 is selected from the group consisting of —OR 7 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, C 3 -C 6 cycloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 1 -C 3 alkoxyC 1 -C 3 alkyl-, hydroxyC 1 -C 6 alkyl-, C 1 -C 3 alkoxyC 1 -C 3 alkoxy-, C 1 -C 6 haloalkoxy, C 1 -C 3 haloalkoxyC 1 -C 3 alkyl-, C 3 -C 6 alkenyloxy and C 3 -C 6 alkynyloxy.
  • R 8 is selected from the group consisting of —OR 7 , C 1 -C 6 alkyl and C 1 -C 6 haloalkyl. More preferably, each R 8 is C 1 -C 6 alky or C 1 -C 6 haloalkyl. Even more preferably still, R 8 is C 1 -C 6 alky. Most preferably R 8 is methyl.
  • R 8a (substituted on a ring nitrogen atom) is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl
  • each R 8b , R 8c and R 8d (substituted on a ring carbon atom) are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, —NH 2 , —S(O) r R 15 , —C(O)OR 10 , —C(O)R 15 , —C(O)NR 16 R 17 , —S(O) 2 NR 16 R 17 , C 1 -C 6 alkyl and C 1 -C 6 haloalkyl.
  • R 8a is hydrogen or C 1 -C 6 alkyl and each R 8b , R 8c and R 8d are independently selected from the group consisting of hydrogen, halogen, cyano, —NH 2 , —C(O)NR 16 R 17 , C 1 -C 6 alkyl and C 1 -C 6 haloalkyl.
  • R 8a is hydrogen or methyl and each R 8b , R 8c and R 8d are independently selected from the group consisting of hydrogen, bromo, chloro, fluoro, cyano, —NH 2 , —C(O)NH 2 , —C(O)NHMe, —C(O)N(Me) 2 , methyl and trifluoromethyl. Even more preferably, R 8a is hydrogen or methyl and each R 8b , R 8c and R 8d are independently selected from the group consisting of hydrogen, bromo, —NH 2 , —C(O)NHMe, methyl and trifluoromethyl. Even more preferably still, R 8a is hydrogen or methyl and each R 8b , R 8c and R 8d are independently selected from the group consisting of hydrogen, —C(O)NHMe, methyl and trifluoromethyl.
  • R 8a (substituted on a ring nitrogen atom) is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl
  • each R 8b , R 8c and R 8d (substituted on a ring carbon atom) are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, —NH 2 , —S(O) r R 15 , —C(O)OR 10 , —C(O)R 15 , —C(O)NR 16 R 17 , —S(O) 2 NR 16 R 17 , C 1 -C 6 alkyl and C 1 -C 6 haloalkyl.
  • R 8a is hydrogen or C 1 -C 6 alkyl and each R 8b , R 8c and R 8d are independently selected from the group consisting of hydrogen, halogen, cyano, —NH 2 , —C(O)NR 16 R 17 , C 1 -C 6 alkyl and C 1 -C 6 haloalkyl.
  • R 8a is hydrogen or methyl and each R 8b , R 8c and R 8d are independently selected from the group consisting of hydrogen, bromo, chloro, fluoro, cyano, —NH 2 , —C(O)NH 2 , —C(O)NHMe, —C(O)N(Me) 2 , methyl and trifluoromethyl. Even more preferably, R 8a is hydrogen or methyl and each R 8b , R 8c and R 8d are independently selected from the group consisting of hydrogen, bromo, —NH 2 , —C(O)NHMe, methyl and trifluoromethyl. Even more preferably still, R 8a is hydrogen or methyl and each R 8b , R 8c and R 8d are independently selected from the group consisting of hydrogen, —C(O)NHMe, methyl and trifluoromethyl.
  • R 8a (substituted on a ring nitrogen atom) is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl
  • each R 8b , R 8c and R 8d (substituted on a ring carbon atom) are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, —NH 2 , —S(O) r R 15 , —C(O)OR 10 , —C(O)R 15 , —C(O)NR 16 R 17 , —S(O) 2 NR 16 R 17 , C 1 -C 6 alkyl and C 1 -C 6 haloalkyl.
  • R 8a is hydrogen or C 1 -C 6 alkyl and each R 8b , R 8c and R 8d are independently selected from the group consisting of hydrogen, halogen, cyano, —NH 2 , —C(O)NR 16 R 17 , C 1 -C 6 alkyl and C 1 -C 6 haloalkyl.
  • R 8a is hydrogen or methyl and each R 8b , R 8c and R 8d are independently selected from the group consisting of hydrogen, bromo, chloro, fluoro, cyano, —NH 2 , —C(O)NH 2 , —C(O)NHMe, —C(O)N(Me) 2 , methyl and trifluoromethyl. Even more preferably, R 8a is hydrogen or methyl and each R 8b , R 8c and R 8d are independently selected from the group consisting of hydrogen, bromo, —NH 2 , —C(O)NHMe, methyl and trifluoromethyl. Even more preferably still, R 8a is hydrogen or methyl and each R 8b , R 8c and R 8d are independently selected from the group consisting of hydrogen, —C(O)NHMe, methyl and trifluoromethyl.
  • each R 8b (substituted on a ring carbon atom) is independently selected from the group consisting of hydrogen, halogen, cyano, —NH 2 , —C(O)NR 16 R 17 , C 1 -C 6 alkyl and C 1 -C 6 haloalkyl.
  • each R 8b is independently selected from the group consisting of hydrogen, bromo, chloro, fluoro, cyano, —NH 2 , —C(O)NH 2 , —C(O)NHMe, —C(O)N(Me) 2 , methyl and trifluoromethyl.
  • each R 8b is independently selected from the group consisting of hydrogen, bromo, —NH 2 , —C(O)NHMe, methyl and trifluoromethyl. Even more preferably, each R 8b is independently selected from the group consisting of hydrogen, —C(O)NHMe, methyl and trifluoromethyl.
  • Each R 9 is independently selected from the group consisting of halogen, cyano, —OH, —N(R 6 ) 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl and C 1 -C 4 haloalkoxy.
  • each R 9 is independently selected from the group consisting of halogen, cyano, —N(R 6 ) 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl and C 1 -C 4 haloalkoxy.
  • each R 9 is independently selected from the group consisting of halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkyl. Even more preferably, each R 9 is independently selected from the group consisting of halogen and C 1 -C 4 alkyl.
  • X is selected from the group consisting of C 3 -C 6 cycloalkyl, phenyl, a 5- or 6-membered heteroaryl, which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, and a 4- to 6-membered heterocyclyl, which comprises 1, 2 or 3 heteroatoms individually selected from N, O and S, and wherein said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties are optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R 9 , and wherein the aforementioned CR 1 R 2 , Q and Z moieties may be attached at any position of said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties.
  • X is selected from the group consisting of phenyl and a 4- to 6-membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O, and wherein said phenyl or heterocyclyl moieties are optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R 9 , and wherein the aforementioned CR 1 R 2 , Q and Z moieties may be attached at any position of said phenyl or heterocyclyl moieties.
  • X is a 4- to 6-membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O, and wherein said heterocyclyl moieties is optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R 9 , and wherein the aforementioned CR 1 R 2 , Q and Z moieties may be attached at any position of said heterocyclyl moiety.
  • X is a 5-membered heterocyclyl, which comprises 1 heteroatom, wherein said heteroatom is N, and wherein the aforementioned CR 1 R 2 , Q and Z moieties may be attached at any position of said heterocyclyl moiety.
  • X is a 5-membered heterocyclyl, which comprises 1 heteroatom, wherein said heteroatom is N, and wherein the aforementioned CR 1 R 2 and Q moieties are attached adjacent to the N atom and the Z moiety is attached to the N atom.
  • X is phenyl optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R 9 , and wherein the aforementioned CR 1 R 2 , Q and Z moieties may be attached at any position of said phenyl moiety.
  • X is phenyl and the aforementioned CR 1 R 2 and Q moieties are attached in a position para to the Z moiety.
  • n is 0 or 1. Preferably, n is 0.
  • Z is selected from the group consisting of —C(O)OR 10 , —CH 2 OH, —CHO, —C(O)NHOR 11 , —C(O)NHCN, —OC(O)NHOR 11 , —OC(O)NHCN, —NR 6 C(O)NHOR 11 , —NR 6 C(O)NHCN, —C(O)NHS(O) 2 R 12 , —OC(O)NHS(O) 2 R 12 , —NR 6 C(O)NHS(O) 2 R 12 , —S(O) 2 OR 10 , —OS(O) 2 OR 10 , —NR 6 S(O) 2 OR 10 , —NR 6 S(O)OR 10 , —NHS(O) 2 R 14 , —S(O)OR 10 , —OS(O)OR 10 , —S(O) 2 NHCN, —S(O) 2 NHC(O)R 18 , —S(
  • Z is selected from the group consisting of —C(O)OR 10 , —C(O)NHOR 11 , —OC(O)NHOR 11 , —NR 6 C(O)NHOR 11 , —C(O)NHS(O) 2 R 12 , —OC(O)NHS(O) 2 R 12 , —NR 6 C(O)NHS(O) 2 R 12 , —S(O) 2 OR 10 , —OS(O) 2 OR 10 , —NR 6 S(O) 2 OR 10 , —NR 6 S(O)OR 10 , —NHS(O) 2 R 14 , —S(O)OR 10 , —OS(O)OR 10 , —OS(O)OR 10 , —S(O) 2 NHC(O)R 18 , —S(O) 2 NHS(O) 2 R 12 , —OS(O) 2 NHS(O) 2 R 12 , —OS(O) 2 NHS(O) 2 R
  • Z is selected from the group consisting of —C(O)OR 10 , —C(O)NHOR 11 , —C(O)NHS(O) 2 R 12 , —S(O) 2 OR 10 , —OS(O) 2 OR 10 , —NR 6 S(O) 2 OR 10 , —NHS(O) 2 R 14 , —S(O)OR 10 and —P(O)(R 13 )(OR 10 ).
  • Z is selected from the group consisting of —C(O)OR 10 , —C(O)NHS(O) 2 R 12 , —S(O) 2 OR 10 , —OS(O) 2 OR 10 and —P(O)(R 13 )(OR 10 ).
  • Z is selected from the group consisting of —C(O)OH, —C(O)OCH 3 , —C(O)OCH 2 CH 3 , —C(O)OCH(CH 3 ) 2 , —C(O)OC(CH 3 ) 3 , —C(O)OCH 2 C 6 H 5 , —C(O)OC 6 H 5 , —C(O)NHS(O) 2 CH 3 , —S(O) 2 OH, —OS(O) 2 OH, —P(O)(OH)(OH), —P(O)(OH)(OCH 2 CH 3 ), —P(O)(OH)(OCH 3 ), —P(O)(OCH 3 )(OCH 3 ), —P(O)(OCH 3 )(OCH 3 ), —P(O)(OCH 2 CH 3 )(OCH 2 CH 3 ), —P(O)(CH 3 )(OH) and —
  • Z is selected from the group consisting of —C(O)OH, —C(O)OCH 3 , —C(O)OCH 2 CH 3 , —C(O)OC(CH 3 ) 3 , —C(O)NHS(O) 2 CH 3 , —S(O) 2 OH, —OS(O) 2 OH, —P(O)(OH)(OH), —P(O)(OH)(OCH 2 CH 3 ), —P(O)(OH)(OCH 3 ), —P(O)(OCH 3 ), —P(O)(OCH 3 )(OCH 3 ), —P(O)(OCH 2 CH 3 )(OCH 2 CH 3 ), —P(O)(CH 3 )(OH) and —P(O)(CH 3 )(OCH 2 CH 3 ).
  • Z is selected from the group consisting of —C(O)OH, —C(O)NHS(O) 2 CH 3 , —S(O) 2 OH, —OS(O) 2 OH, —P(O)(OH)(OH), —P(O)(OH)(OCH 2 CH 3 ), —P(O)(OH)(OCH 3 ) and —P(O)(CH 3 )(OH).
  • Z is —C(O)OH or —S(O) 2 OH.
  • Z is selected from the group consisting of —C(O)OR 10 , —C(O)NHS(O) 2 R 12 , —S(O) 2 OR 10 , and —P(O)(R 13 )(OR 10 ) (preferably, —C(O)OH, —C(O)OCH 3 , —C(O)OCH 2 CH 3 , —C(O)NHS(O) 2 CH 3 , —S(O) 2 OH, —P(O)(OH)(OH), —P(O)(OH)(OCH 2 CH 3 ), —P(O)(CH 3 )(OH) and —P(O)(CH 3 )(OCH 2 CH 3 )).
  • R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, phenyl and benzyl, and wherein said phenyl or benzyl are optionally substituted by 1, 2 or 3 R 9 substituents, which may be the same or different.
  • R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, phenyl and benzyl. More preferably, R 10 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl. Even more preferably, R 10 is selected from the group consisting of hydrogen, methyl, ethyl and tert-butyl. Most preferably, R 10 is hydrogen.
  • R 11 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R 9 substituents, which may be the same or different.
  • R 11 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and phenyl. More preferably, R 11 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl. Even more preferably, R 11 is C 1 -C 6 alkyl. Most preferably, R 11 is methyl.
  • R 12 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —OH, —N(R 6 ) 2 and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R 9 substituents, which may be the same or different.
  • R 12 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —OH, —N(R 6 ) 2 and phenyl.
  • R 12 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and —N(R 6 ) 2 . Even more preferably, R 12 is selected from the group consisting of methyl, —N(Me) 2 and trifluoromethyl. Most preferably, R 12 is methyl.
  • R 13 is selected from the group consisting of —OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and phenyl.
  • R 13 is selected from the group consisting of —OH, C 1 -C 6 alkyl and C 1 -C 6 alkoxy. More preferably, R 13 is selected from the group consisting of —OH and C 1 -C 6 alkoxy. Even more preferably, R 13 is selected from the group consisting of —OH, methoxy and ethoxy. Most preferably, R 13 is —OH.
  • R 14 is C 1 -C 6 haloalkyl. Preferably, R 14 is trifluoromethyl.
  • R 15 is selected from the group consisting of C 1 -C 6 alkyl and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R 9 substituents, which may be the same or different.
  • R 15 is selected from the group consisting of C 1 -C 6 alkyl and phenyl. More preferably, R 15 is C 1 -C 6 alkyl. Most preferably R 15 is methyl.
  • R 15a is phenyl, wherein said phenyl is optionally substituted by 1, 2 or 3 R 9 substituents, which may be the same or different.
  • R 15a is phenyl optionally substituted by 1 R 9 substituent. More preferably, R 15a is phenyl.
  • R 16 and R 17 are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl. Preferably, R 16 and R 17 are independently selected from the group consisting of hydrogen and methyl.
  • R 16 and R 17 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S.
  • R 16 and R 17 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N and O.
  • R 16 and R 17 together with the nitrogen atom to which they are attached form an pyrrolidyl, oxazolidinyl, imidazolidinyl, piperidyl, piperazinyl or morpholinyl group.
  • R 18 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —N(R 6 ) 2 and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R 9 substituents, which may be the same or different.
  • R 18 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —N(R 6 ) 2 and phenyl.
  • R 18 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl. Further more preferably, R 18 is selected from the group consisting of C 1 -C 6 alkyl and C 1 -C 6 haloalkyl. Most preferably, R 18 is methyl or trifluoromethyl.
  • r is 0, 1 or 2.
  • r is 0 or 2.
  • R 1 is hydrogen or C 1 -C 6 alkyl
  • R 2 is hydrogen or methyl
  • Q is (CR 1a R 2b ) m
  • m is 0, 1 or 2
  • R 1a and R 2b are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, —OH and —NH 2
  • R 3 , R 3a , R 4 and R 5 are independently selected from the group consisting of hydrogen, chloro, fluoro, bromo and methyl
  • each R 6 is independently selected from hydrogen and methyl
  • each R 7 is C 1 -C 6 alkyl
  • A is a 5-membered heteroaryl attached to the rest of the molecule via a ring carbon atom, which comprises 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S, and wherein the heteroaryl may, where feasible, be optionally substituted by 1, 2 or 3 R 8 substituents, which may be the same or different;
  • each R 8 is independently selected from the group consisting of halogen, nitro, cyano, —NH 2 , —S(O) r R 15 , —C(O)OR 10 , —C(O)R 15 , —C(O)NR 16 R 17 , —S(O) 2 NR 16 R 17 , C 1 -C 6 alkyl and C 1 -C 6 haloalkyl; and/or when A is substituted on a ring nitrogen atom, R 8 is C 1 -C 6 alky or C 1 -C 6 haloalkyl; and n is 0; Z is selected from the group consisting of —C(O)OR 10 , —C(O)NHS(O) 2 R 12 , —S(O) 2 OR 10 , —OS(O) 2 OR 10 and —P(O)(R 13 )(OR 10 ); R 10 is selected from the group consisting of —C(O)OR 10 , —C
  • R 1 is hydrogen or methyl
  • R 2 is hydrogen or methyl
  • Q is (CR 1a R 2b ) m
  • m is 0 or 1
  • R 1a and R 2b are independently selected from the group consisting of hydrogen and methyl
  • R 3 , R 3a , R 4 and R 5 are independently selected from the group consisting of hydrogen, chloro and fluoro
  • A is a heteroaryl selected from the group consisting of 1,2,4-oxadiazol-5-yl, thiadiazol-5-yl, 1,2,4-thiadiazol-5-yl, thiadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,5-thiadiazol-3-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,5-oxadiazol-3-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-3-yl, 1,
  • the compound according to formula (I) is selected from a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e) or (I-f),
  • each R 8b is independently selected from the group consisting of hydrogen, bromo, chloro, fluoro, cyano, —NH 2 , —C(O)NH 2 , —C(O)NHMe, —C(O)N(Me) 2 , methyl and trifluoromethyl; and Z is selected from the group consisting of —C(O)OH, —C(O)OCH 3 , —C(O)OCH 2 CH 3 , —C(O)OC(CH 3 ) 3 , —C(O)NHS(O) 2 CH 3 , —S(O) 2 OH, —OS(O) 2 OH, —P(O)(OH)(OH), —P(O)(OH)(OCH 2 CH 3 ), —P(O)(OH)(OCH 3 ), —P(O)(OH)(OCH 3 ), —P(O)(OH)(OCH 3 ), —P(O)(OH
  • the compound according to formula (I) is selected from a compound of formula (I-aa), (I-bb), (I-cc), (I-dd), (I-ee) or (I-ff),
  • Z is —C(O)OH or —S(O) 2 OH.
  • the compound according to formula (I) is selected from a compound of formula (I-h), (I-k) or (I-m),
  • R 1 is hydrogen or methyl
  • R 2 is hydrogen or methyl
  • R 3 , R 3a , R 4 and R 5 are independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, cyano, methyl and trifluoromethyl
  • each R 6 is independently hydrogen or methyl
  • each R 8b is independently selected from the group consisting of hydrogen, halogen, cyano, —NH 2 , —C(O)NR 16 R 17 , C 1 -C 6 alkyl and C 1 -C 6 haloalkyl
  • Z is selected from the group consisting of —C(O)OR 10 , —C(O)NHS(O) 2 R 12 , —S(O) 2 OR 10 , and —P(O)(R 13 )(OR 10 );
  • R 10 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
  • R 12 is selected from the group consisting of the group consisting of the group consisting of hydrogen
  • the compound according to formula (I) is selected from a compound A1 to A101 listed in Table A.
  • compounds of formula (I) may exist/be manufactured in ‘procidal form’, wherein they comprise a group ‘G’. Such compounds are referred to herein as compounds of formula (I-IV).
  • G is a group which may be removed in a plant by any appropriate mechanism including, but not limited to, metabolism and chemical degradation to give a compound of formula (I-I), (I-II) or (I-III) wherein Z contains an acidic proton, for example see the scheme below:
  • Z-G may include but is not limited to, any one of (G1) to (G7) below and E indicates the point of attachment to the remaining part of a compound of formula (I):
  • G, R 19 , R 20 , R 21 , R 22 and R 23 are defined as follows:
  • G is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —C(R 21 R 22 )OC(O)R 19 , phenyl or phenyl-C 1 -C 4 alkyl-, wherein said phenyl moiety is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 alkoxy.
  • R 19 is C 1 -C 6 alkyl or phenyl
  • R 20 is hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or phenyl
  • R 21 is hydrogen or methyl
  • R 22 is hydrogen or methyl
  • R 23 is hydrogen or C 1 -C 6 alkyl.
  • the compounds of the present invention may be prepared according to the following schemes in which the substituents n, m, r, A, Q, X, Z, R 1 , R 2 , R 1a , R 2b , R 2 , R 3 , R 3a , R 4 , R 5 , R 6 , R 7 , R 7a , R 7b , R 7c , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 15a , R 16 , R 17 and R 18 are as defined hereinbefore unless explicitly stated otherwise.
  • the compounds of the preceeding Tables 1 to 27 may thus be obtained in an analogous manner.
  • the compounds of formula (I) may be prepared by the alkylation of compounds of formula (X), wherein R 3 , R 3a , R 4 , R 5 and A are as defined for compounds of formula (I), with a suitable alkylating agent of formula (W), wherein R 1 , R 2 , Q, X, n and Z are as defined for compounds of formula (I) and LG is a suitable leaving group, for example, halide or pseudohalide such as triflate, mesylate or tosylate, in a suitable solvent at a suitable temperature, as described in reaction scheme 1.
  • Example conditions include stirring a compound of formula (X) with an alkylating agent of formula (W) in a solvent, or mixture of solvents, such as acetone, dichloromethane, dichloroethane, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, water, acetic acid or trifluroacetic acid at a temperature between ⁇ 78° C. and 150° C.
  • solvent such as acetone, dichloromethane, dichloroethane, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, water, acetic acid or trifluroacetic acid at a temperature between ⁇ 78° C. and 150° C.
  • An alkylating agent of formula (W) may include, but is not limited to, bromoacetic acid, methyl bromoacetate, 3-bromopropionoic acid, methyl 3-bromopropionate, 2-bromo-N-methoxyacetamide, sodium 2-bromoethanesulphonate, 2,2-dimethylpropyl 2-(trifluoromethylsulfonyloxy)ethanesulfonate, 2-bromo-N-methanesulfonylacetamide, 3-bromo-N-methanesulfonylpropanamide, dimethoxyphosphorylmethyl trifluoromethanesulfonate, dimethyl 3-bromopropylphosphonate, 3-chloro-2,2-dimethyl-propanoic acid and diethyl 2-bromoethylphosphonate.
  • esters of N-alkyl acids which include, but are not limited to, esters of carboxylic acids, phosphonic acids, phosphinic acids, sulfonic acids and sulfinic acids, may be subsequently partially or fully hydrolysed by treament with a suitable reagent, for example, aqueous hydrochloric acid or trimethylsilyl bromide, in a suitable solvent at a suitable temperature between 0° C. and 100° C.
  • a suitable reagent for example, aqueous hydrochloric acid or trimethylsilyl bromide
  • compounds of formula (I) may be prepared by reacting compounds of formula (X), wherein R 3 , R 3a , R 4 , R 5 and A are as defined for compounds of formula (I), with a suitably activated electrophilic alkene of formula (B), wherein Z is —S(O) 2 OR 10 , —P(O)(R 13 )(OR 10 ) or —C(O)OR 10 and R 1 , R 2 , R 1a , R 10 and R 13 are as defined for compounds of formula (I), in a suitable solvent at a suitable temperature.
  • Compounds of formula (B) are known in the literature, or may be prepared by known methods.
  • Example reagents include, but are not limited to, acrylic acid, methacrylic acid, crotonic acid, 3,3-dimethylacrylic acid, methyl acrylate, ethene sulfonic acid, isopropyl ethylenesulfonate, 2,2-dimethylpropyl ethenesulfonate and dimethyl vinylphosphonate.
  • esters of N-alkyl acids which include, but are not limited to, esters of carboxylic acids, phosphonic acids, phosphinic acids, sulfonic acids and sulfinic acids, may be subsequently partially or fully hydrolysed by treament with a suitable reagent in a suitable solvent at a suitable temperature, as described in reaction scheme 2.
  • An alkylating agent of formula (E) or (F) may include, but is not limited to, 1,3-propanesultone, 1,4-butanesultone, ethylenesulfate, 1,3-propylene sulfate and 1,2,3-oxathiazolidine 2,2-dioxide.
  • Such alkylating agents and related compounds are either known in the literature or may be prepared by known literature methods.
  • a compound of formula (I), wherein m is 0, n is 0 and Z is —S(O) 2 OH may be prepared from a compound of formula (I), wherein m is 0, n is 0 and Z is C(O)OR 10 , by treatment with trimethylsilylchlorosulfonate in a suitable solvent at a suitable temperature, as described in reaction scheme 4.
  • Preferred conditions include heating the carboxylate precursor in neat trimethylsilylchlorosulfonate at a temperature between 25° C. and 150° C.
  • compounds of formula (I) may be prepared by reacting compounds of formula (X), wherein R 3 , R 3a , R 4 , R 5 and A are as defined for compounds of formula (I), with a suitable alcohol of formula (WV), wherein R 1 , R 2 , Q, X, n and Z are as defined for compounds of formula (I), under Mitsunobu-type conditions such as those reported by Petit et al, Tet. Lett. 2008, 49 (22), 3663.
  • Suitable phosphines include triphenylphosphine
  • suitable azodicarboxylates include diisopropylazodicarboxylate
  • suitable acids include fluoroboric acid, triflic acid and bis(trifluoromethylsulfonyl)amine, as described in reaction scheme 5.
  • Such alcohols are either known in the literature or may be prepared by known literature methods.
  • a compound of formula (I), wherein n, Q, Z, X, R 1 , R 2 , R 3 , R 3a , R 4 , R 5 and A are as defined for compounds of formula (I), may be prepared from a compound of formula (R) and an oxidant, in a suitable solvent at a suitable temperature, as outlined in reaction scheme 6.
  • oxidants include, but are not limited to, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, tetrachloro-p-benzoquinone, potassium permanganate, manganese dioxide, 2,2,6,6-tetramethyl-1-piperidinyloxy and bromine.
  • Related reactions are known in the literature.
  • a compound of formula (R), wherein n, Q, Z, X, R 1 , R 2 , R 3 , R 3a , R 4 , R 5 and A are as defined for compounds of formula (I), may be prepared from a compound of formula (S) and an organometallic of formula (T), wherein M′ includes, but is not limited to, organomagnesium, organolithium, organocopper and organozinc reagents, in a suitable solvent at a suitable temperature, optionally in the presence of an additional transition metal additive, as outlined in reaction scheme 7.
  • Example conditions include treating a compound of formula (S) with a Grignard of formula (T), in the presence of 0.05-100 mol % copper iodide, in a solvent such as tetrahydrofuran at a temperature between ⁇ 78° C. and 100° C.
  • Organometallics of formula (T) are known in the literature, or may be prepared by known literature methods.
  • Compounds of formula (S) may be prepared by analogous reactions to those for the preparation of compounds of formula (I) from a compound of formula (XX).
  • Biaryl pyridines of formula (X) are known in the literature or may be prepared using literature methods.
  • Example methods include, but are not limited to, the transition metal cross-coupling of compounds of formula (H) and formula (J), or alternatively compounds of formula (K) and formula (L), in which compounds of formula (J) and formula (L), wherein M′ is either an organostannane, organoboronic acid or ester, organotrifluoroborate, organomagnesium, organocopper or organozinc, as outlined in reaction scheme 8.
  • Hal is defined as a halogen or pseudo halogen, for example triflate, mesylate and tosylate.
  • Such cross-couplings include Stille (for example Sauer, J.; Heldmann, D. K.
  • Suzuki-Miyaura for example Luebbers, T.; Flohr, A.; Jolidon, S.; David-Pierson, P.; Jacobsen, H.; Ozmen, L.; Baumann, K. Bioorg. Med. Chem. Lett., 2011, 6554
  • Negishi for example Imahori, T.; Suzawa, K.; Kondo, Y. Heterocycles, 2008, 1057
  • Kumada for example Heravi, M. M.; Hajiabbasi, P. Monatsh. Chem., 2012, 1575.
  • the coupling partners may be selected with reference to the specific cross-coupling reaction and target product.
  • Transition metal catalysts may be selected with reference to the desired cross-coupling and are known in the literature.
  • Compounds of formula (H), formula (K) and formula (L) are known in the literature, or may be prepared by known literature methods.
  • a compound of formula (J), wherein M′ is either an organostannane, organoboronic acid or ester, organotrifluoroborate, organomagnesium, organocopper or organozinc, may be prepared from a compound of formula (XX), wherein R 3 , R 3a , R 4 and R 5 are as defined for compounds of formula (I), by metalation, as outlined in reaction scheme 9. Similar reactions are known in the literature (for example Ramphal et al, WO2015/153683, Unsinn et al., Organic Letters, 15(5), 1128-1131; 2013, Sadler et al., Organic & Biomolecular Chemistry, 12(37), 7318-7327; 2014.
  • an organometallic of formula (J) may be prepared from compounds of formula (K), wherein R 3 , R 3a , R 4 and R 5 are as defined for compounds of formula (I), and Hal is defined as a halogen or pseudo halogen, for example triflate, mesylate and tosylate, as described in scheme 9.
  • Example conditions to prepare an compound of formula (J) wherein M′ is an organostannane include treatment of a compound of formula (K) with lithium tributyl tin in an appropriate solvent at an appropriate temperature (for example see WO 2010/038465).
  • Example conditions to prepare compound of formula (J) wherein M′ is an organoboronic acid or ester include treatment of a compound of formula (K) with bis(pinacolato)diboron, in the presence of an appropriate transition metal catalyst, appropriate ligand, appropriate base, in an appropriate solvent at an appropriate temperature (for example KR 2015135626).
  • Compounds of formula (K) and formula (XX) are either known in the literature or can be prepared by known methods.
  • biaryl pyridines of formula (X) may be prepared by classical ring synthesis approaches starting from a compound of formula (ZZ), wherein R 3 , R 3a , R 4 and R 5 are as defined for compounds of formula (I) and T is a functional group which can be converted through one or more chemical steps into a 5-membered heteroaryl A, wherein A is as defined for compounds of formula (I).
  • Such functional groups include, but are not limited to, acid, ester, nitrile, amide, thioamide and ketone.
  • Related transformations are known in the literature.
  • Substituted pyridines may be prepared using methodology outlined in the literature.
  • the compounds according to the invention can be used as herbicidal agents in unmodified form, but they are generally formulated into compositions in various ways using formulation adjuvants, such as carriers, solvents and surface-active substances.
  • formulation adjuvants such as carriers, solvents and surface-active substances.
  • the formulations can be in various physical forms, e.g.
  • Such formulations can either be used directly or diluted prior to use.
  • the dilutions can be made, for example, with water, liquid fertilisers, micronutrients, biological organisms, oil or solvents.
  • the formulations can be prepared e.g. by mixing the active ingredient with the formulation adjuvants in order to obtain compositions in the form of finely divided solids, granules, solutions, dispersions or emulsions.
  • the active ingredients can also be formulated with other adjuvants, such as finely divided solids, mineral oils, oils of vegetable or animal origin, modified oils of vegetable or animal origin, organic solvents, water, surface-active substances or combinations thereof.
  • the active ingredients can also be contained in very fine microcapsules.
  • Microcapsules contain the active ingredients in a porous carrier. This enables the active ingredients to be released into the environment in controlled amounts (e.g. slow-release).
  • Microcapsules usually have a diameter of from 0.1 to 500 microns. They contain active ingredients in an amount of about from 25 to 95% by weight of the capsule weight.
  • the active ingredients can be in the form of a monolithic solid, in the form of fine particles in solid or liquid dispersion or in the form of a suitable solution.
  • the encapsulating membranes can comprise, for example, natural or synthetic rubbers, cellulose, styrene/butadiene copolymers, polyacrylonitrile, polyacrylate, polyesters, polyamides, polyureas, polyurethane or chemically modified polymers and starch xanthates or other polymers that are known to the person skilled in the art.
  • very fine microcapsules can be formed in which the active ingredient is contained in the form of finely divided particles in a solid matrix of base substance, but the microcapsules are not themselves encapsulated.
  • liquid carriers there may be used: water, toluene, xylene, petroleum ether, vegetable oils, acetone, methyl ethyl ketone, cyclohexanone, acid anhydrides, acetonitrile, acetophenone, amyl acetate, 2-butanone, butylene carbonate, chlorobenzene, cyclohexane, cyclohexanol, alkyl esters of acetic acid, diacetone alcohol, 1,2-dichloropropane, diethanolamine, p-diethylbenzene, diethylene glycol, diethylene glycol abietate, diethylene glycol butyl ether, diethylene glycol ethyl ether, diethylene glycol methyl ether, N,N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, dipropylene glycol
  • Suitable solid carriers are, for example, talc, titanium dioxide, pyrophyllite clay, silica, attapulgite clay, kieselguhr, limestone, calcium carbonate, bentonite, calcium montmorillonite, cottonseed husks, wheat flour, soybean flour, pumice, wood flour, ground walnut shells, lignin and similar substances.
  • a large number of surface-active substances can advantageously be used in both solid and liquid formulations, especially in those formulations which can be diluted with a carrier prior to use.
  • Surface-active substances may be anionic, cationic, non-ionic or polymeric and they can be used as emulsifiers, wetting agents or suspending agents or for other purposes.
  • Typical surface-active substances include, for example, salts of alkyl sulfates, such as diethanolammonium lauryl sulfate; salts of alkylarylsulfonates, such as calcium dodecylbenzenesulfonate; alkylphenol/alkylene oxide addition products, such as nonylphenol ethoxylate; alcohol/alkylene oxide addition products, such as tridecylalcohol ethoxylate; soaps, such as sodium stearate; salts of alkylnaphthalenesulfonates, such as sodium dibutylnaphthalenesulfonate; dialkyl esters of sulfosuccinate salts, such as sodium di(2-ethylhexyl)sulfosuccinate; sorbitol esters, such as sorbitol oleate; quaternary amines, such as lauryltrimethylammonium chloride, polyethylene glycol esters of fatty
  • Further adjuvants that can be used in pesticidal formulations include crystallisation inhibitors, viscosity modifiers, suspending agents, dyes, anti-oxidants, foaming agents, light absorbers, mixing auxiliaries, antifoams, complexing agents, neutralising or pH-modifying substances and buffers, corrosion inhibitors, fragrances, wetting agents, take-up enhancers, micronutrients, plasticisers, glidants, lubricants, dispersants, thickeners, antifreezes, microbicides, and liquid and solid fertilisers.
  • compositions according to the invention can include an additive comprising an oil of vegetable or animal origin, a mineral oil, alkyl esters of such oils or mixtures of such oils and oil derivatives.
  • the amount of oil additive in the composition according to the invention is generally from 0.01 to 10%, based on the mixture to be applied.
  • the oil additive can be added to a spray tank in the desired concentration after a spray mixture has been prepared.
  • Preferred oil additives comprise mineral oils or an oil of vegetable origin, for example rapeseed oil, olive oil or sunflower oil, emulsified vegetable oil, alkyl esters of oils of vegetable origin, for example the methyl derivatives, or an oil of animal origin, such as fish oil or beef tallow.
  • Preferred oil additives comprise alkyl esters of C 8 -C 22 fatty acids, especially the methyl derivatives of C 12 -C 18 fatty acids, for example the methyl esters of lauric acid, palmitic acid and oleic acid (methyl laurate, methyl palmitate and methyl oleate, respectively).
  • Many oil derivatives are known from the Compendium of Herbicide Adjuvants, 10 th Edition, Southern Illinois University, 2010.
  • the herbicidal compositions generally comprise from 0.1 to 99% by weight, especially from 0.1 to 95% by weight, compounds of formula (I) and from 1 to 99.9% by weight of a formulation adjuvant which preferably includes from 0 to 25% by weight of a surface-active substance.
  • the inventive compositions generally comprise from 0.1 to 99% by weight, especially from 0.1 to 95% by weight, of compounds of the present invention and from 1 to 99.9% by weight of a formulation adjuvant which preferably includes from 0 to 25% by weight of a surface-active substance. Whereas commercial products may preferably be formulated as concentrates, the end user will normally employ dilute formulations.
  • the rates of application vary within wide limits and depend on the nature of the soil, the method of application, the crop plant, the pest to be controlled, the prevailing climatic conditions, and other factors governed by the method of application, the time of application and the target crop.
  • a general guideline compounds may be applied at a rate of from 1 to 2000 I/ha, especially from 10 to 1000 I/ha.
  • Preferred formulations can have the following compositions (weight %):
  • Emulsifiable concentrates active ingredient: 1 to 95%, preferably 60 to 90% surface-active agent: 1 to 30%, preferably 5 to 20% liquid carrier: 1 to 80%, preferably 1 to 35%
  • active ingredient 0.1 to 10%, preferably 0.1 to 5% solid carrier: 99.9 to 90%, preferably 99.9 to 99%
  • Suspension concentrates active ingredient: 5 to 75%, preferably 10 to 50% water: 94 to 24%, preferably 88 to 30% surface-active agent: 1 to 40%, preferably 2 to 30%
  • Wettable powders active ingredient: 0.5 to 90%, preferably 1 to 80% surface-active agent: 0.5 to 20%, preferably 1 to 15% solid carrier: 5 to 95%, preferably 15 to 90%
  • active ingredient 0.1 to 30%, preferably 0.1 to 15% solid carrier: 99.5 to 70%, preferably 97 to 85%
  • composition of the present may further comprise at least one additional pesticide.
  • additional pesticide is a herbicide and/or herbicide safener.
  • compounds of formula (I) can be used in combination with one or more other herbicides to provide various herbicidal mixtures.
  • specific examples of such mixtures include (wherein “I” represents a compound of formula (I)):—I+acetochlor, I+acifluorfen (including acifluorfen-sodium), I+aclonifen, I+ametryn, I+amicarbazone, I+aminopyralid, I+aminotriazole, I+atrazine, I+beflubutamid-M, I+bensulfuron (including bensulfuron-methyl), I+bentazone, I+bicyclopyrone, I+bilanafos, I+bispyribac-sodium, I+bixlozone, I+bromacil, I+bromoxynil, I+butachlor, I+butafenacil, I+carfentrazone (including carfentrazone-ethyl), I+clorans
  • the mixing partners of the compound of formula (I) may also be in the form of esters or salts, as mentioned e.g. in The Pesticide Manual, Fourteenth Edition, British Crop Protection Council, 2006.
  • the compound of formula (I) can also be used in mixtures with other agrochemicals such as fungicides, nematicides or insecticides, examples of which are given in The Pesticide Manual.
  • the mixing ratio of the compound of formula (I) to the mixing partner is preferably from 1:100 to 1000:1.
  • mixtures can advantageously be used in the above-mentioned formulations (in which case “active ingredient” relates to the respective mixture of compound of formula (I) with the mixing partner).
  • Compounds of formula (I) of the present invention may also be combined with herbicide safeners.
  • Preferred combinations include:—I+benoxacor, I+cloquintocet (including cloquintocet-mexyl); I+cyprosulfamide; I+dichlormid; I+fenchlorazole (including fenchlorazole-ethyl); I+fenclorim; I+fluxofenim; 1+furilazole I+isoxadifen (including isoxadifen-ethyl); I+mefenpyr (including mefenpyr-diethyl); I+metcamifen and I+oxabetrinil.
  • the safeners of the compound of formula (I) may also be in the form of esters or salts, as mentioned e.g. in The Pesticide Manual, 14 th Edition (BCPC), 2006.
  • the reference to cloquintocet-mexyl also applies to a lithium, sodium, potassium, calcium, magnesium, aluminium, iron, ammonium, quaternary ammonium, sulfonium or phosphonium salt thereof as disclosed in WO 02/34048, and the reference to fenchlorazole-ethyl also applies to fenchlorazole, etc.
  • the mixing ratio of compound of formula (I) to safener is from 100:1 to 1:10, especially from 20:1 to 1:1.
  • mixtures can advantageously be used in the above-mentioned formulations (in which case “active ingredient” relates to the respective mixture of compound of formula (I) with the safener).
  • the compounds of formula (I) of this invention are useful as herbicides.
  • the present invention therefore further comprises a method for controlling unwanted plants comprising applying to the said plants or a locus comprising them, an effective amount of a compound of the invention or a herbicidal composition containing said compound.
  • Controlling means killing, reducing or retarding growth or preventing or reducing germination.
  • the plants to be controlled are unwanted plants (weeds).
  • Locus means the area in which the plants are growing or will grow.
  • the rates of application of compounds of formula (I) may vary within wide limits and depend on the nature of the soil, the method of application (pre-emergence; post-emergence; application to the seed furrow; no tillage application etc.), the crop plant, the weed(s) to be controlled, the prevailing climatic conditions, and other factors governed by the method of application, the time of application and the target crop.
  • the compounds of formula (I) according to the invention are generally applied at a rate of from 10 to 2000 g/ha, especially from 50 to 1000 g/ha.
  • the application is generally made by spraying the composition, typically by tractor mounted sprayer for large areas, but other methods such as dusting (for powders), drip or drench can also be used.
  • composition according to the invention can be used include crops such as cereals, for example barley and wheat, cotton, oilseed rape, sunflower, maize, rice, soybeans, sugar beet, sugar cane and turf.
  • crops such as cereals, for example barley and wheat, cotton, oilseed rape, sunflower, maize, rice, soybeans, sugar beet, sugar cane and turf.
  • Crop plants can also include trees, such as fruit trees, palm trees, coconut trees or other nuts. Also included are vines such as grapes, fruit bushes, fruit plants and vegetables.
  • Crops are to be understood as also including those crops which have been rendered tolerant to herbicides or classes of herbicides (e.g. ALS-, GS-, EPSPS-, PPO-, ACCase- and HPPD-inhibitors) by conventional methods of breeding or by genetic engineering.
  • herbicides or classes of herbicides e.g. ALS-, GS-, EPSPS-, PPO-, ACCase- and HPPD-inhibitors
  • An example of a crop that has been rendered tolerant to imidazolinones, e.g. imazamox, by conventional methods of breeding is Clearfield® summer rape (canola).
  • crops that have been rendered tolerant to herbicides by genetic engineering methods include e.g. glyphosate- and glufosinate-resistant maize varieties commercially available under the trade names RoundupReady® and LibertyLink®.
  • Crops are also to be understood as being those which have been rendered resistant to harmful insects by genetic engineering methods, for example Bt maize (resistant to European corn borer), Bt cotton (resistant to cotton boll weevil) and also Bt potatoes (resistant to Colorado beetle).
  • Bt maize are the Bt 176 maize hybrids of NK® (Syngenta Seeds).
  • the Bt toxin is a protein that is formed naturally by Bacillus thuringiensis soil bacteria.
  • Examples of toxins, or transgenic plants able to synthesise such toxins are described in EP-A-451 878, EP-A-374 753, WO 93/07278, WO 95/34656, WO 03/052073 and EP-A-427 529.
  • transgenic plants comprising one or more genes that code for an insecticidal resistance and express one or more toxins are KnockOut® (maize), Yield Gard® (maize), NuCOTIN33B® (cotton), Bollgard® (cotton), NewLeaf® (potatoes), NatureGard® and Protexcta®.
  • Plant crops or seed material thereof can be both resistant to herbicides and, at the same time, resistant to insect feeding (“stacked” transgenic events).
  • seed can have the ability to express an insecticidal Cry3 protein while at the same time being tolerant to glyphosate.
  • Crops are also to be understood to include those which are obtained by conventional methods of breeding or genetic engineering and contain so-called output traits (e.g. improved storage stability, higher nutritional value and improved flavour).
  • output traits e.g. improved storage stability, higher nutritional value and improved flavour.
  • turf grass for example in golf-courses, lawns, parks and roadsides, or grown commercially for sod
  • ornamental plants such as flowers or bushes.
  • Compounds of formula (I) and compositions of the invention can typically be used to control a wide variety of monocotyledonous and dicotyledonous weed species.
  • monocotyledonous species that can typically be controlled include Alopecurus myosuroides, Avena fatua, Brachiaria plantaginea, Bromus tectorum, Cyperus esculentus, Digitaria sanguinalis, Echinochloa crus - galli, Lolium perenne, Lolium multiflorum, Panicum miliaceum, Poa annua, Setaria viridis, Setaria faberi and Sorghum bicolor .
  • dicotyledonous species that can be controlled include Abutilon theophrasti, Amaranthus retroflexus, Bidens pilosa, Chenopodium album, Euphorbia heterophylla, Galium aparine, Ipomoea hederacea, Kochia scoparia, Polygonum convolvulus, Sida spinosa, Sinapis arvensis, Solanum nigrum, Stellaria media, Veronica persica and Xanthium strumarium.
  • the compounds of formula (I) are also useful for pre-harvest desiccation in crops, for example, but not limited to, potatoes, soybean, sunflowers and cotton.
  • Pre-harvest desiccation is used to desiccate crop foliage without significant damage to the crop itself to aid harvesting.
  • Compounds/compositions of the invention are particularly useful in non-selective burn-down applications, and as such may also be used to control volunteer or escape crop plants.
  • Wettable powders a) b) c) active ingredients 25% 50% 75% sodium lignosulfonate 5% 5% — sodium lauryl sulfate 3% — 5% sodium diisobutylnaphthalenesulfonate — 6% 10% phenol polyethylene glycol ether — 2% — (7-8 mol of ethylene oxide) highly dispersed silicic acid 5% 10% 10% Kaolin 62% 27% —
  • the combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording wettable powders that can be diluted with water to give suspensions of the desired concentration.
  • Emulsions of any required dilution which can be used in plant protection, can be obtained from this concentrate by dilution with water.
  • Dusts a) b) c) Active ingredients 5% 6% 4% Talcum 95% — — Kaolin — 94% — mineral filler — — 96%
  • the combination is mixed and ground with the adjuvants, and the mixture is moistened with water.
  • the mixture is extruded and then dried in a stream of air.
  • the finely ground combination is uniformly applied, in a mixer, to the kaolin moistened with polyethylene glycol.
  • Non-dusty coated granules are obtained in this manner.
  • the finely ground combination is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water.
  • 28 parts of the combination are mixed with 2 parts of an aromatic solvent and 7 parts of toluene diisocyanate/polymethylene-polyphenylisocyanate-mixture (8:1).
  • This mixture is emulsified in a mixture of 1.2 parts of polyvinylalcohol, 0.05 parts of a defoamer and 51.6 parts of water until the desired particle size is achieved.
  • a mixture of 2.8 parts 1,6-diaminohexane in 5.3 parts of water is added. The mixture is agitated until the polymerization reaction is completed.
  • the obtained capsule suspension is stabilized by adding 0.25 parts of a thickener and 3 parts of a dispersing agent.
  • the capsule suspension formulation contains 28% of the active ingredients.
  • the medium capsule diameter is 8-15 microns.
  • the resulting formulation is applied to seeds as an aqueous suspension in an apparatus suitable for that purpose.
  • Electrospray positive and negative Cone (V) 20.00, Source Temperature (° C.) 120, Cone Gas Flow (L/Hr.) 50
  • the preparative HPLC was conducted using an 11.4 minute run time (not using at column dilution, bypassed with the column selector), according to the following gradient table:
  • Step 1 Preparation of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridin-1-ium chloride
  • Step 2 Preparation of tert-butyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]acetate
  • Step 3 Preparation of tert-butyl 2-[4-[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]-3,6-dihydro-2H-pyridin-1-yl]acetate
  • reaction mixture was cooled to room temperature then filtered through diatomaceous earth and partitioned between water and ethyl acetate.
  • the organic phase was concentrated then purified by silica gel chromatography eluting with 0 to 50% ethyl acetate in cyclohexane to give tert-butyl 2-[4-[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]-3,6-dihydro-2H-pyridin-1-yl]acetate.
  • Step 4 Preparation of 2-[4-[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]pyridin-1-ium-1-yl]acetic acid 2,2,2-trifluoroacetate A1
  • reaction mixture was diluted with tert-butyl methyl ether (20 mL) and the resulting solid was filtered, washed with additional tert-butyl methyl ether then purified by preparative reverse phase HPLC (trifluoroacetic acid was present in the eluent) to afford 2-[4-[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]pyridin-1-ium-1-yl]acetic acid 2,2,2-trifluoroacetate.
  • Step 3 Preparation of methyl 2-[4-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]acetate bromide
  • Step 4 Preparation of 2-[4-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]acetic acid chloride A59
  • Step 5 Preparation of [4-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]methanesulfonate A2
  • Step 1 Preparation of methyl 2-diazo-3-oxo-3-(4-pyridyl)propanoate
  • Step 1 Preparation of methyl 3-[4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]propanoate 2,2,2-trifluoroacetate
  • Step 1 Preparation of tert-butyl 4-(1,2,4-thiadiazol-5-yl)-3,6-dihydro-2H-pyridine-1-carboxylate
  • Step 3 Preparation of sodium [4-(1,2,4-thiadiazol-5-yl)-3,6-dihydro-2H-pyridin-1-yl]methanesulfonate
  • N-(dimethylaminomethylene)pyridine-4-carboxamide (3.99 g) was added a solution of dioxane (27 mL), hydroxylamine (50% aqueous solution, 2.07 mL) and acetic acid (32 mL). The mixture was heated at 90° C. for 1 hour. The reaction mixture was concentrated and partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane. The organic layer was concentrated and purified by preparative reverse phase HPLC to give 5-(4-pyridyl)-1,2,4-oxadiazole as a white solid.
  • the material is isolated as a mixture with 4-(I-methyltetrazol-5-yl)pyridine.
  • reaction mixture was poured into water and extracted with dichloromethane (2 ⁇ 50 mL). The combined organic layers were washed with 1M aqueous hydrochloric acid (50 mL), dried over sodium sulfate and concentrated to afford dimethoxyphosphorylmethyl trifluoromethanesulfonate as pale yellow liquid.
  • Step 3 Preparation of 5-[1-(dimethoxyphosphorylmethyl)pyridin-1-ium-4-yl]-1,2,4-thiadiazole trifluoromethanesulfonate A77
  • the water layer was concentrated and purified by reverse phase HPLC (100% water) to afford 5-[1-(dimethoxyphosphorylmethyl)pyridin-1-ium-4-yl]-1,2,4-thiadiazole trifluoromethanesulfonate as a light brown solid.
  • Step 4 Preparation of methoxy-[[4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]methyl]phosphinate A30
  • the water layer was concentrated and purified by reverse phase HPLC (100% water) to give methoxy-[[4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]methyl]phosphinate as an off-white solid.
  • Step 3 Preparation of 5-[1-[[ethoxy(methyl)phosphoryl]methyl]pyridin-1-ium-4-yl]-1,2,4-thiadiazole trifluoromethanesulfonate A47
  • the water layer was concentrated and purified by reverse phase HPLC (100% water) to afford 5-[1-[[ethoxy(methyl)phosphoryl]methyl]pyridin-1-ium-4-yl]-1,2,4-thiadiazole trifluoromethanesulfonate as a brown solid.
  • Step 4 Preparation of methyl-[[4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]methyl]phosphinate A10
  • Step 1 Preparation of ethyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]propanoate
  • Step 2 Preparation of ethyl 3-[4-[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]-3,6-dihydro-2H-pyridin-1-yl]propanoate
  • reaction mixture was cooled to room temperature then filtered through diatomaceous earth.
  • the filtrate was concentrated then purified by silica gel chromatography eluting with a mixture of ethyl acetate in cyclohexane to give ethyl 3-[4-[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]-3,6-dihydro-2H-pyridin-1-yl]propanoate.
  • Step 3 Preparation of 3-[4-[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]pyridin-1-ium-1-yl]propanoic acid acetate A48
  • Step 3 Preparation of 3-[4-(3-hydroxy-1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]propanoic acid bromide A97
  • Step 5 Preparation of 3-[3-methylsulfonyl-4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]propanoic acid bromide A93
  • Seeds of a variety of test species were sown in standard loam based soil in pots. Plants were cultivated from between 21 and 28 days (post-emergence) under controlled conditions in a glasshouse (at 24/16° C., day/night; 14 hours light; 65% humidity) for warm climate species and (at 20/16° C. day/night; 15 hours light; 65% humidity) for cool climate species.
  • IF50 11.12% Emulsogen EL360 TM+44.44% N-methylpyrrolidone+44.44% Dowanol DPM glycol ether
  • IF50 11.12% Emulsogen EL360 TM+44.44% N-methylpyrrolidone+44.44% Dowanol DPM glycol ether
  • the delivery of the aqueous spray solution was via a laboratory track sprayer which delivered the aqueous spray composition at a rate of 200 litres per hectare, using a flat fan nozzle (Teejet 11002VS) and an application volume of 200 litre/ha (at 2 bar).
  • a laboratory track sprayer which delivered the aqueous spray composition at a rate of 200 litres per hectare, using a flat fan nozzle (Teejet 11002VS) and an application volume of 200 litre/ha (at 2 bar).
  • Ipomoea hederacea IPHE
  • Euphorbia heterophylla EPHHL
  • Chenopodium album CHEAL
  • Amaranthus palmeri AMAPA
  • Lolium perenne LLOLPE
  • Digitaria sanguinalis DIGSA
  • Eleusine indica ELEIN
  • Echinochloa crus - galli EHCG
  • Setaria faberi SETFA
  • Brassica napus (BRSNN), Solanum turberosum (SOLTU), Glycine Max (GLXMA), and Helianthus annus (HELAN)

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Abstract

Compounds of the formula (I) wherein the substituents are as defined in claim 1, useful as a pesticides, especially as herbicides.
Figure US20220104493A1-20220407-C00001

Description

  • The present invention relates to herbicidally active pyridinium derivatives, as well as to processes and intermediates used for the preparation of such derivatives. The invention further extends to herbicidal compositions comprising such derivatives, as well as to the use of such compounds and compositions for controlling undesirable plant growth: in particular the use for controlling weeds, in crops of useful plants.
  • The present invention is based on the finding that pyridinium derivatives of formula (I) as defined herein, exhibit surprisingly good herbicidal activity. Thus, according to the present invention there is provided the use of a compound of formula (I) or an agronomically acceptable salt or zwitterionic species thereof, as a herbicide:
  • Figure US20220104493A1-20220407-C00002
  • wherein
    R1 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C1-C6haloalkyl, —OR7, —OR15a, —N(R6)S(O)2R15, —N(R6)C(O)R15, —N(R6)C(O)OR15, —N(R6)C(O)NR16R17, —N(R6)CHO, —N(R7a)2 and —S(O)rR15;
    R2 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl and C1-C6haloalkyl;
    and wherein when R1 is selected from the group consisting of —OR7, —OR15a, —N(R6)S(O)2R15, —N(R6)C(O)R15, —N(R6)C(O)OR15, —N(R6)C(O)NR16R17, —N(R6)CHO, —N(R7a)2 and —S(O)rR15, R2 is selected from the group consisting of hydrogen and C1-C6alkyl; or
    R1 and R2 together with the carbon atom to which they are attached form a C3-C6cycloalkyl ring or a 3- to 6-membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O; and

  • Q is (CR1aR2b)m;
  • m is 0, 1, 2 or 3;
    each R1a and R2b are independently selected from the group consisting of hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, —OH, —OR7, —OR15a, —NH2, —NHR7, —NHR15a, —N(R6)CHO, —NR7bR7c and —S(O)rR15; or
    each R1a and R2b together with the carbon atom to which they are attached form a C3-C6cycloalkyl ring or a 3- to 6-membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O; and
    R3, R3a, R4 and R5 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, —S(O)rR15, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6fluoroalkoxy, C1-C6alkoxy, C3-C6cycloalkyl and —N(R6)2;
    each R6 is independently selected from hydrogen and C1-C6alkyl;
    each R7 is independently selected from the group consisting of C1-C6alkyl, —S(O)2R15, —C(O)R15, —C(O)OR15 and —C(O)NR16R17;
    each R7a is independently selected from the group consisting of —S(O)2R15, —C(O)R15, —C(O)OR15, —C(O)NR16R17 and —C(O)NR6R15a;
    R7b and R7c are independently selected from the group consisting of C1-C6alkyl, —S(O)2R15, —C(O)R15, —C(O)OR15, —C(O)NR16R17 and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R9 substituents, which may be the same or different; or
    R7b and R7c together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S; and
    A is a 5-membered heteroaryl attached to the rest of the molecule via a ring carbon atom, which comprises 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S, and wherein the heteroaryl may, where feasible, be optionally substituted by 1, 2 or 3 R8 substituents, which may be the same or different,
    and wherein when A is substituted on one or more ring carbon atoms, each R8 is independently selected from the group consisting of halogen, nitro, cyano, —NH2, —NHR7, —N(R7)2, —OH, —OR7, —S(O)rR15, —NR6S(O)2R15, —C(O)OR10, —C(O)R15, —C(O)NR16R17, —S(O)2NR16R17, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C3-C6halocycloalkyl, C3-C6cycloalkoxy, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, C1-C3alkoxyC1-C3alkyl-, hydroxyC1-C6alkyl-, C1-C3alkoxyC1-C3alkoxy-, C1-C6haloalkoxy, C1-C3haloalkoxyC1-C3alkyl-, C3-C6alkenyloxy, C3-C6alkynyloxy, N—C3-C6cycloalkylamino, —C(R6)═NOR6, phenyl, a 3- to 6-membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O, and a 5- or 6-membered heteroaryl, which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, and wherein said phenyl, heterocyclyl or heteroaryl are optionally substituted by 1, 2 or 3 R9 substituents, which may be the same or different;
    and/or
    when A is substituted on a ring nitrogen atom, R8 is selected from the group consisting of —OR7, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C3-C6halocycloalkyl, C3-C6cycloalkoxy, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, C1-C3alkoxyC1-C3alkyl-, hydroxyC1-C6alkyl-, C1-C3alkoxyC1-C3alkoxy-, C1-C6haloalkoxy, C1-C3haloalkoxyC1-C3alkyl-, C3-C6alkenyloxy and C3-C6alkynyloxy; and
    each R9 is independently selected from the group consisting of halogen, cyano, —OH, —N(R6)2, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl and C1-C4haloalkoxy;
    X is selected from the group consisting of C3-C6cycloalkyl, phenyl, a 5- or 6-membered heteroaryl, which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, and a 4- to 6-membered heterocyclyl, which comprises 1, 2 or 3 heteroatoms individually selected from N, O and S, and wherein said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties are optionally substituted by 1 or 2 R9 substituents, and wherein the aforementioned CR1R2, Q and Z moieties may be attached at any position of said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties;
    n is 0 or 1;
    Z is selected from the group consisting of —C(O)OR10, —CH2OH, —CHO, —C(O)NHOR11, —C(O)NHCN, —OC(O)NHOR11, —OC(O)NHCN, —NR6C(O)NHOR11, —NR6C(O)NHCN, —C(O)NHS(O)2R12, —OC(O)NHS(O)2R12, —NR6C(O)NHS(O)2R12, —S(O)2OR10, —OS(O)2OR10, —NR6S(O)2OR10, —NR6S(O)OR10, —NHS(O)2R14, —S(O)OR10, —OS(O)OR10, —S(O)2NHCN, —S(O)2NHC(O)R18, —S(O)2NHS(O)2R12, —OS(O)2NHCN, —OS(O)2NHS(O)2R12, —OS(O)2NHC(O)R18, —NR6S(O)2NHCN, —NR6S(O)2NHC(O)R1, —N(OH)C(O)R15, —ONHC(O)R15, —NR6S(O)2NHS(O)2R12, —P(O)(R13)(OR10), —P(O)H(OR10), —OP(O)(R13)(OR10), —NR6P(O)(R13)(OR10) and tetrazole;
    R10 is selected from the group consisting of hydrogen, C1-C6alkyl, phenyl and benzyl, and wherein said phenyl or benzyl are optionally substituted by 1, 2 or 3 R9 substituents, which may be the same or different;
    R11 is selected from the group consisting of hydrogen, C1-C6alkyl and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R9 substituents, which may be the same or different;
    R12 is selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, —OH, —N(R6)2 and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R9 substituents, which may be the same or different;
    R13 is selected from the group consisting of —OH, C1-C6alkyl, C1-C6alkoxy and phenyl;
    R14 is C1-C6haloalkyl;
    R15 is selected from the group consisting of C1-C6alkyl and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R9 substituents, which may be the same or different;
    R15a is phenyl, wherein said phenyl is optionally substituted by 1, 2 or 3 R9 substituents, which may be the same or different;
    R16 and R17 are independently selected from the group consisting of hydrogen and C1-C6alkyl; or
    R16 and R17 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S; and
    R18 is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, —N(R6)2 and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R9 substituents, which may be the same or different;
    and
    r is 0, 1 or 2.
  • Certain compounds of formula (I) are known (or an agronomically acceptable salt or zwitterionic species thereof):
  • Figure US20220104493A1-20220407-C00003
    Figure US20220104493A1-20220407-C00004
  • Thus in a second aspect of the invention there is provided a compound of formula (I) wherein:
      • i) A is not selected from the group consisting of formula A-Ib to A-IIIb below
  • Figure US20220104493A1-20220407-C00005
      • wherein each R8b′ is independently selected from the group consisting of phenyl, 4-methoxyphenyl, 4-butoxyphenyl, 4-fluorophenyl and methoxy, and each R8c′ is independently hydrogen or methyl;
      • or
      • ii) the compound of formula (I) is not selected from the group consisting of ethyl 2-[4-(2-thienyl)pyridin-1-ium-1-yl]acetate, ethyl 2-[4-(5-methyl-1H-pyrazol-3-yl)pyridin-1-ium-1-yl]acetate, 2-[4-[5-(I-ethylpyridin-1-ium-4-yl)-2-furyl]pyridin-1-ium-1-yl]ethylphosphonic acid, 2-[4-[4-(I-ethylpyridin-1-ium-4-yl)-3-thienyl]pyridin-1-ium-1-yl]ethylphosphonic acid and 3-[4-[5-[4-(dihexylamino)phenyl]-2-thienyl]pyridin-1-ium-1-yl]propane-1-sulfonic acid shown above
  • According to a third aspect of the invention there is provided an agrochemical composition comprising a herbicidally effective amount of a compound of formula (I) and an agrochemically-acceptable diluent or carrier. Such an agricultural composition may further comprise at least one additional active ingredient.
  • According to a fourth aspect of the invention, there is provided a method of controlling or preventing undesirable plant growth, wherein a herbicidally effective amount of a compound of formula (I), or a composition comprising this compound as active ingredient, is applied to the plants, to parts thereof or the locus thereof.
  • According to a fifth aspect of the invention, there is provided the use of a compound of formula (I) as defined herein for pre-harvest desiccation in crops.
  • As used herein, the term “halogen” or “halo” refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo), preferably fluorine, chlorine or bromine.
  • As used herein, cyano means a —CN group.
  • As used herein, hydroxy means an —OH group.
  • As used herein, nitro means an —NO2 group.
  • As used herein, the term “C1-C6alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond. C1-C4alkyl and C1-C2alkyl are to be construed accordingly. Examples of C1-C6alkyl include, but are not limited to, methyl (Me), ethyl (Et), n-propyl, 1-methylethyl (iso-propyl), n-butyl, and 1-dimethylethyl (t-butyl).
  • As used herein, the term “C1-C6alkoxy” refers to a radical of the formula —ORa where Ra is a C1-C6alkyl radical as generally defined above. C1-C4alkoxy is to be construed accordingly. Examples of C1-4alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy and t-butoxy.
  • As used herein, the term “C1-C6haloalkyl” refers to a C1-C6alkyl radical as generally defined above substituted by one or more of the same or different halogen atoms. C1-C4haloalkyl is to be construed accordingly. Examples of C1-C6haloalkyl include, but are not limited to chloromethyl, fluoromethyl, fluoroethyl, difluoromethyl, trifluoromethyl and 2,2,2-trifluoroethyl.
  • As used herein, the term “C2-C6alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond that can be of either the (E)- or (Z)-configuration, having from two to six carbon atoms, which is attached to the rest of the molecule by a single bond. C2-C4alkenyl is to be construed accordingly. Examples of C2-C6alkenyl include, but are not limited to, prop-1-enyl, allyl (prop-2-enyl) and but-1-enyl.
  • As used herein, the term “C2-C6haloalkenyl” refers to a C2-C6alkenyl radical as generally defined above substituted by one or more of the same or different halogen atoms. Examples of C2-C6haloalkenyl include, but are not limited to chloroethylene, fluoroethylene, 1,1-difluoroethylene, 1,1-dichloroethylene and 1,1,2-trichloroethylene.
  • As used herein, the term “C2-C6alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to six carbon atoms, and which is attached to the rest of the molecule by a single bond. C2-C4alkynyl is to be construed accordingly. Examples of C2-C6alkynyl include, but are not limited to, prop-1-ynyl, propargyl (prop-2-ynyl) and but-1-ynyl.
  • As used herein, the term “C1-C6haloalkoxy” refers to a C1-C6alkoxy group as defined above substituted by one or more of the same or different halogen atoms. C1-C4haloalkoxy is to be construed accordingly. Examples of C1-C5haloalkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, fluoroethoxy, trifluoromethoxy and trifluoroethoxy.
  • As used herein, the term “C1-C3haloalkoxyC1-C3alkyl” refers to a radical of the formula Rb—O—Ra— where Rb is a C1-C3haloalkyl radical as generally defined above, and Ra is a C1-C3alkylene radical as generally defined above.
  • As used herein, the term “C1-C3alkoxyC1-C3alkyl” refers to a radical of the formula Rb—O—Ra— where Rb is a C1-C3alkyl radical as generally defined above, and Ra is a C1-C3alkylene radical as generally defined above.
  • As used herein, the term “C1-C3alkoxyC1-C3alkoxy-” refers to a radical of the formula Rb—O—Ra—O— where Rb is a C1-C3alkyl radical as generally defined above, and Ra is a C1-C3alkylene radical as generally defined above.
  • As used herein, the term “C3-C6alkenyloxy” refers to a radical of the formula —ORa where Ra is a C3-C6alkenyl radical as generally defined above.
  • As used herein, the term “C3-C6alkynyloxy” refers to a radical of the formula —ORa where Ra is a C3-C6alkynyl radical as generally defined above.
  • As used herein, the term “hydroxyC1-C6alkyl” refers to a C1-C6alkyl radical as generally defined above substituted by one or more hydroxy groups.
  • As used herein, the term “C1-C6alkylcarbonyl” refers to a radical of the formula —C(O)Ra where Ra is a C1-C6alkyl radical as generally defined above.
  • As used herein, the term “C1-C6alkoxycarbonyl” refers to a radical of the formula —C(O)ORa where Ra is a C1-C6alkyl radical as generally defined above.
  • As used herein, the term “aminocarbonyl” refers to a radical of the formula —C(O)NH2.
  • As used herein, the term “C3-C6cycloalkyl” refers to a stable, monocyclic ring radical which is saturated or partially unsaturated and contains 3 to 6 carbon atoms. C3-C4cycloalkyl is to be construed accordingly. Examples of C3-C6cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • As used herein, the term “C3-C6halocycloalkyl” refers to a C3-C6cycloalkyl radical as generally defined above substituted by one or more of the same or different halogen atoms. C3-C4halocycloalkyl is to be construed accordingly.
  • As used herein, the term “C3-C6cycloalkoxy” refers to a radical of the formula —ORa where Ra is a C3-C6cycloalkyl radical as generally defined above.
  • As used herein, the term “N—C3-C6cycloalkylamino” refers to a radical of the formula —NHRa where Ra is a C3-C6cycloalkyl radical as generally defined above.
  • As used herein, except where explicitly stated otherwise, the term “heteroaryl” refers to a 5- or 6-membered monocyclic aromatic ring which comprises 1, 2, 3 or 4 heteroatoms individually selected from nitrogen, oxygen and sulfur. The heteroaryl radical may be bonded to the rest of the molecule via a carbon atom or heteroatom. Examples of heteroaryl include, furyl, pyrrolyl, imidazolyl, thienyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidyl or pyridyl.
  • As used herein, except where explicitly stated otherwise, the term “heterocyclyl” or “heterocyclic” refers to a stable 4- to 6-membered non-aromatic monocyclic ring radical which comprises 1, 2, or 3 heteroatoms individually selected from nitrogen, oxygen and sulfur. The heterocyclyl radical may be bonded to the rest of the molecule via a carbon atom or heteroatom. Examples of heterocyclyl include, but are not limited to, pyrrolinyl, pyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydrothiopyranyl, piperidyl, piperazinyl, tetrahydropyranyl, dihydroisoxazolyl, dioxolanyl, morpholinyl or δ-lactamyl.
  • The presence of one or more possible asymmetric carbon atoms in a compound of formula (I) means that the compounds may occur in chiral isomeric forms, i.e., enantiomeric or diastereomeric forms. Also atropisomers may occur as a result of restricted rotation about a single bond. formula (I) is intended to include all those possible isomeric forms and mixtures thereof. The present invention includes all those possible isomeric forms and mixtures thereof for a compound of formula (I). Likewise, formula (I) is intended to include all possible tautomers (including lactam-lactim tautomerism and keto-enol tautomerism) where present. The present invention includes all possible tautomeric forms for a compound of formula (I). Similarly, where there are di-substituted alkenes, these may be present in E or Z form or as mixtures of both in any proportion. The present invention includes all these possible isomeric forms and mixtures thereof for a compound of formula (I).
  • The compounds of formula (I) will typically be provided in the form of an agronomically acceptable salt, a zwitterion or an agronomically acceptable salt of a zwitterion. This invention covers all such agronomically acceptable salts, zwitterions and mixtures thereof in all proportions.
  • For example a compound of formula (I) wherein Z comprises an acidic proton, may exist as a zwitterion, a compound of formula (I-I), or as an agronomically acceptable salt, a compound of formula (I-II) as shown below:
  • Figure US20220104493A1-20220407-C00006
  • wherein, Y represents an agronomically acceptable anion and j and k represent integers that may be selected from 1, 2 or 3, dependent upon the charge of the respective anion Y.
  • A compound of formula (I) may also exist as an agronomically acceptable salt of a zwitterion, a compound of formula (I-Ill) as shown below:
  • Figure US20220104493A1-20220407-C00007
  • wherein, Y represents an agronomically acceptable anion, M represents an agronomically acceptable cation (in addition to the pyridinium cation) and the integers j, k and q may be selected from 1, 2 or 3, dependent upon the charge of the respective anion Y and respective cation M.
  • Thus where a compound of formula (I) is drawn in protonated form herein (for example a compound of formula (I-II)), the skilled person would appreciate that it could equally be represented in unprotonated or salt form with one or more relevant counter ions.
  • In one embodiment of the invention there is provided a compound of formula (I-II) wherein k is 2, j is 1 and Y is selected from the group consisting of halogen, trifluoroacetate and pentafluoropropionate. In this embodiment a nitrogen atom in the ring A may be protonated or a nitrogen atom comprised in R1, R2, Q or X may be protonated. Preferably, in a compound of formula (I-II), k is 2, j is 1 and Y is chloride, wherein a nitrogen atom in the ring comprising A is protonated.
  • Suitable agronomically acceptable salts of the present invention, represented by an anion Y, include but are not limited chloride, bromide, iodide, fluoride, 2-naphthalenesulfonate, acetate, adipate, methoxide, ethoxide, propoxide, butoxide, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, butylsulfate, butylsulfonate, butyrate, camphorate, camsylate, caprate, caproate, caprylate, carbonate, citrate, diphosphate, edetate, edisylate, enanthate, ethanedisulfonate, ethanesulfonate, ethylsulfate, formate, fumarate, gluceptate, gluconate, glucoronate, glutamate, glycerophosphate, heptadecanoate, hexadecanoate, hydrogen sulfate, hydroxide, hydroxynaphthoate, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methanedisulfonate, methylsulfate, mucate, myristate, napsylate, nitrate, nonadecanoate, octadecanoate, oxalate, pelargonate, pentadecanoate, pentafluoropropionate, perchlorate, phosphate, propionate, propylsulfate, propylsulfonate, succinate, sulfate, tartrate, tosylate, tridecylate, triflate, trifluoroacetate, undecylinate and valerate.
  • Suitable cations represented by M include, but are not limited to, metals, conjugate acids of amines and organic cations. Examples of suitable metals include aluminium, calcium, cesium, copper, lithium, magnesium, manganese, potassium, sodium, iron and zinc. Examples of suitable amines include allylamine, ammonia, amylamine, arginine, benethamine, benzathine, butenyl-2-amine, butylamine, butylethanolamine, cyclohexylamine, decylamine, diamylamine, dibutylamine, diethanolamine, diethylamine, diethylenetriamine, diheptylamine, dihexylamine, diisoamylamine, diisopropylamine, dimethylamine, dioctylamine, dipropanolamine, dipropargylamine, dipropylamine, dodecylamine, ethanolamine, ethylamine, ethylbutylamine, ethylenediamine, ethylheptylamine, ethyloctylamine, ethylpropanolamine, heptadecylamine, heptylamine, hexadecylamine, hexenyl-2-amine, hexylamine, hexylheptylamine, hexyloctylamine, histidine, indoline, isoamylamine, isobutanolamine, isobutylamine, isopropanolamine, isopropylamine, lysine, meglumine, methoxyethylamine, methylamine, methylbutylamine, methylethylamine, methylhexylamine, methylisopropylamine, methylnonylamine, methyloctadecylamine, methylpentadecylamine, morpholine, N,N-diethylethanolamine, N-methylpiperazine, nonylamine, octadecylamine, octylamine, oleylamine, pentadecylamine, pentenyl-2-amine, phenoxyethylamine, picoline, piperazine, piperidine, propanolamine, propylamine, propylenediamine, pyridine, pyrrolidine, sec-butylamine, stearylamine, tallowamine, tetradecylamine, tributylamine, tridecylamine, trimethylamine, triheptylamine, trihexylamine, triisobutylamine, triisodecylamine, triisopropylamine, trimethylamine, tripentylamine, tripropylamine, tris(hydroxymethyl)aminomethane, and undecylamine. Examples of suitable organic cations include benzyltributylammonium, benzyltrimethylammonium, benzyltriphenylphosphonium, choline, tetrabutylammonium, tetrabutylphosphonium, tetraethylammonium, tetraethylphosphonium, tetramethylammonium, tetramethylphosphonium, tetrapropylammonium, tetrapropylphosphonium, tributylsulfonium, tributylsulfoxonium, triethylsulfonium, triethylsulfoxonium, trimethylsulfonium, trimethylsulfoxonium, tripropylsulfonium and tripropylsulfoxonium.
  • Preferred compounds of formula (I), wherein Z comprises an acidic proton, can be represented as either (I-I) or (I-II). For compounds of formula (I-II) emphasis is given to salts when Y is chloride, bromide, iodide, hydroxide, bicarbonate, acetate, pentafluoropropionate, triflate, trifluoroacetate, methylsulfate, tosylate and nitrate, wherein j and k are 1. Preferably, Y is chloride, bromide, iodide, hydroxide, bicarbonate, acetate, trifluoroacetate, methylsulfate, tosylate and nitrate, wherein j and k are 1. For compounds of formula (I-II) emphasis is also given to salts when Y is carbonate and sulfate, wherein j is 2 and k is 1, and when Y is phosphate, wherein j is 3 and k is 1.
  • Where appropriate compounds of formula (I) may also be in the form of (and/or be used as) an N-oxide. Compounds of formula (I) wherein m is 0 and n is 0 may be represented by a compound of formula (I-Ia) as shown below:
  • Figure US20220104493A1-20220407-C00008
  • wherein R1, R2, R3, R3a, R4, R5, A and Z are as defined for compounds of formula (I).
  • Compounds of formula (I) wherein m is 1 and n is 0 may be represented by a compound of formula (I-Ib) as shown below:
  • Figure US20220104493A1-20220407-C00009
  • wherein R1, R2, R1a, R2b, R3, R3a, R4, R5, A and Z are as defined for compounds of formula (I).
  • Compounds of formula (I) wherein m is 2 and n is 0 may be represented by a compound of formula (I-Ic) as shown below:
  • Figure US20220104493A1-20220407-C00010
  • wherein R1, R2, R1a, R2b, R3, R3a, R4, R5, A and Z are as defined for compounds of formula (I).
  • Compounds of formula (I) wherein m is 3 and n is 0 may be represented by a compound of formula (I-Id) as shown below:
  • Figure US20220104493A1-20220407-C00011
  • wherein R1, R2, R1a, R2b, R3, R3a, R4, R5, A and Z are as defined for compounds of formula (I).
  • The following list provides definitions, including preferred definitions, for substituents n, m, r, A, Q, X, Z, R1, R2, R1a, R2, R2, R3, R3, R4, R5, R6, R7, R7b, R7b, R7c, R8, R9, R10, R11, R12, R13, R14, R15, R15a, R16, R17 and R18 with reference to the compounds of formula (I) according to the invention. For any one of these substituents, any of the definitions given below may be combined with any definition of any other substituent given below or elsewhere in this document.
  • R1 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C1-C6haloalkyl, —OR7, —OR15a, —N(R6)S(O)2R15, —N(R6)C(O)R15, —N(R6)C(O)OR15, —N(R6)C(O)NR16R17, —N(R6)CHO, —N(R7a)2 and —S(O)rR15. Preferably, R1 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl, C1-C6fluoroalkyl, —OR7, —NHS(O)2R15, —NHC(O)R15, —NHC(O)OR15, —NHC(O)NR16R17, —N(R7a)2 and —S(O)rR15. More preferably, R1 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl, C1-C6fluoroalkyl, —OR7 and —N(R7a)2. Even more preferably, R1 is selected from the group consisting of hydrogen, halogen and C1-C6alkyl. Even more preferably still, R1 is hydrogen or C1-C6alkyl. Yet even more preferably still, R1 is hydrogen or methyl. Most preferably R1 is hydrogen.
  • R2 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl and C1-C6haloalkyl. Preferably, R2 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl and C1-C6fluoroalkyl. More preferably, R2 is hydrogen or C1-C6alkyl. Even more preferably, R2 is hydrogen or methyl. Most preferably R2 is hydrogen.
  • Wherein when R1 is selected from the group consisting of —OR7, —OR15a, —N(R6)S(O)2R15, —N(R6)C(O)R15, —N(R6)C(O)OR15, —N(R6)C(O)NR16R17, —N(R6)CHO, —N(R7a)2 and —S(O)rR15, R2 is selected from the group consisting of hydrogen and C1-C6alkyl. Preferably, when R1 is selected from the group consisting of —OR7, —NHS(O)2R15, —NHC(O)R15, —NHC(O)OR15, —NHC(O)NR16R17, —N(R7a)2 and —S(O)rR15, R2 is selected from the group consisting of hydrogen and methyl.
  • Alternatively, R1 and R2 together with the carbon atom to which they are attached form a C3-C6cycloalkyl ring or a 3- to 6-membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O. Preferably, R1 and R2 together with the carbon atom to which they are attached form a C3-C6cycloalkyl ring. More preferably, R1 and R2 together with the carbon atom to which they are attached form a cyclopropyl ring.
  • In one embodiment R1 and R2 are hydrogen.
  • In another embodiment R1 is methyl and R2 is hydrogen.
  • In another embodiment R1 is methyl and R2 is methyl.
  • Q is (CR1aR2b)m.
    m is 0, 1, 2 or 3. Preferably, m is 0, 1 or 2. More preferably, m is 0 or 1. Most preferably, m is 0.
  • Each R1a and R2b are independently selected from the group consisting of hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, —OH, —OR7, —OR15a, —NH2, —NHR7, —NHR15a, —N(R6)CHO, —NR7bR7c and —S(O)rR15. Preferably, each R1a and R2b are independently selected from the group consisting of hydrogen, halogen, C1-C6alkyl, C1-C6fluoroalkyl, —OH, —NH2 and —NHR7. More preferably, each Ria and R2b are independently selected from the group consisting of hydrogen, C1-C6alkyl, —OH and —NH2. Even more preferably, each R1a and R2b are independently selected from the group consisting of hydrogen, methyl, —OH and —NH2. Even more preferably still, each R1a and R2b are independently selected from the group consisting of hydrogen and methyl. Most preferably R1a and R2b are hydrogen.
  • In another embodiment each R1a and R2b are independently selected from the group consisting of hydrogen and C1-C6alkyl.
  • Alternatively, each R1a and R2b together with the carbon atom to which they are attached form a C3-C6cycloalkyl ring or a 3- to 6-membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O. Preferably, each R1a and R2b together with the carbon atom to which they are attached form a C3-C6cycloalkyl ring. More preferably, each R1a and R2b together with the carbon atom to which they are attached form a cyclopropyl ring.
  • R3, R3a, R4 and R5 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, —S(O)rR15, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6fluoroalkoxy, C1-C6alkoxy, C3-C6cycloalkyl and —N(R6)2. Preferably, R3, R3a, R4 and R5 are independently selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6fluoroalkoxy, C1-C6alkoxy, C3-C6cycloalkyl and —N(R6)2. More preferably, R3, R3a, R4 and R5 are independently selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl and C1-C6fluoroalkyl. Even more preferably, R3, R3a, R4 and R5 are independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, cyano, methyl and trifluoromethyl. Even more preferably still, R3, R3a, R4 and R5 are independently selected from the group consisting of hydrogen, chloro, fluoro, bromo and methyl. Yet even more preferably still, R3, R3a, R4 and R5 are independently selected from the group consisting of hydrogen, chloro and fluoro. Most preferably, R3, R3a, R4 and R5 are hydrogen.
  • In one embodiment R3 and R3a are hydrogen, and R4 and R5 are independently selected from the group consisting of hydrogen, bromo, chloro, fluoro and —S(O)2Me (preferably, hydrogen, chloro and fluoro).
  • Each R6 is independently selected from hydrogen and C1-C6alkyl. Preferably, each R6 is independently selected from hydrogen and methyl.
  • Each R7 is independently selected from the group consisting of C1-C6alkyl, —S(O)2R15, —C(O)R15, —C(O)OR15 and —C(O)NR16R17. Preferably, each R7 is independently selected from the group consisting of C1-C6alkyl, —C(O)R15 and —C(O)NR16R17. More preferably, each R7 is C1-C6alkyl. Most preferably, each R7 is methyl.
  • Each R7a is independently selected from the group consisting of —S(O)2R15, —C(O)R15, —C(O)OR15, —C(O)NR16R17 and —C(O)NR6R15a. Preferably, each R7a is independently —C(O)R15 or —C(O)NR16R17.
  • R7b and R7c are independently selected from the group consisting of C1-C6alkyl, —S(O)2R15, —C(O)R15, —C(O)OR15, —C(O)NR16R17 and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R9 substituents, which may be the same or different. Preferably, R7b and R7c are independently selected from the group consisting of C1-C6alkyl, —C(O)R15 and —C(O)NR16R17. More preferably, R7b and R7c are C1-C6alkyl. Most preferably, R7b and R7c are methyl.
  • Alternatively, R7b and R7c together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S. Preferably, R7b and R7c together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N and O. More preferably, R7b and R7c together with the nitrogen atom to which they are attached form an pyrrolidyl, oxazolidinyl, imidazolidinyl, piperidyl, piperazinyl or morpholinyl group.
  • A is a 5-membered heteroaryl attached to the rest of the molecule via a ring carbon atom, which comprises 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S, and wherein the heteroaryl may, where feasible, be optionally substituted by 1, 2 or 3 R8 substituents, which may be the same or different.
  • Preferably, A is a heteroaryl selected from the group consisting of 1,2,4-oxadiazol-5-yl, thiadiazol-5-yl, 1,2,4-thiadiazol-5-yl, thiadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,5-thiadiazol-3-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,5-oxadiazol-3-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, triazol-4-yl, triazol-5-yl, 2-methyltetrazol-5-yl, 1-methyltetrazol-5-yl, thiazol-2-yl, thiazol-4-yl, isothiazol-5-yl, isothiazol-4-yl, isothiazol-3-yl, oxazol-2-yl, oxazol-4-yl, isoxazol-3-yl, isoxazol-5-yl, imidazol-5-yl, imidazol-2-yl, 3-furyl, 2-furyl, 3-thienyl, pyrazol-5-yl, pyrazol-3-yl and 2-thienyl wherein the heteroaryl may, where feasible, be optionally substituted by 1, 2 or 3 R8 substituents, which may be the same or different.
  • More preferably, A is selected from the group consisting of formula A-I to A-XXXV below
  • Figure US20220104493A1-20220407-C00012
    Figure US20220104493A1-20220407-C00013
    Figure US20220104493A1-20220407-C00014
    Figure US20220104493A1-20220407-C00015
  • wherein the jagged line defines the point of attachment to a compound of formula (I), and R8a, R8b, R8c, R8d, R10, R15, R16, R17 and r are as defined herein. R8a, R8b, R8c, R8d are examples of R8 wherein the subscript letter a, b, c and d are used to denote positions within individual heterocycles (A-I to A-XXXV).
  • Even more preferably, A is selected from the group consisting of formula A-I to A-XXXII below
  • Figure US20220104493A1-20220407-C00016
    Figure US20220104493A1-20220407-C00017
    Figure US20220104493A1-20220407-C00018
    Figure US20220104493A1-20220407-C00019
  • wherein the jagged line defines the point of attachment to a compound of formula (I), and R8a, R8b, R8c, R8d, R10, R11, R16, R17 and r are as defined herein.
  • Even more preferably still, A is selected from the group consisting of formula A-1 to A-X, A-XVII, A-XVIII, A-XIX, A-XXIII, A-XXIV and AXXVII below
  • Figure US20220104493A1-20220407-C00020
    Figure US20220104493A1-20220407-C00021
  • wherein the jagged line defines the point of attachment to a compound of formula (I), and
    R8a, R8b, R8c, R8d, R10, R15, R16, R17 and r are as defined herein.
  • Yet even more preferably still, A is selected from the group consisting of formula A-I to A-III below
  • Figure US20220104493A1-20220407-C00022
  • wherein the jagged line defines the point of attachment to a compound of formula (I), and each R8b and R16 and R17 are as defined herein.
  • Further more preferably still, A is selected from the group consisting of formula A-Ia to A-Xa below
  • Figure US20220104493A1-20220407-C00023
  • wherein the jagged line defines the point of attachment to a compound of formula (I).
  • In one embodiment, A is selected from the group consisting of formula A-Ia to A-XXXXVIIa below
  • Figure US20220104493A1-20220407-C00024
    Figure US20220104493A1-20220407-C00025
    Figure US20220104493A1-20220407-C00026
    Figure US20220104493A1-20220407-C00027
    Figure US20220104493A1-20220407-C00028
  • wherein the jagged line defines the point of attachment to a compound of formula (I).
  • When A is substituted on one or more ring carbon atoms, each R8 is independently selected from the group consisting of halogen, nitro, cyano, —NH2, —NHR7, —N(R7)2, —OH, —OR7, —S(O)rR15, —NR6S(O)2R15, —C(O)OR10, —C(O)R15, —C(O)NR16R17, —S(O)2NR16R17, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C3-C6halocycloalkyl, C3-C6cycloalkoxy, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, C1-C3alkoxyC1-C3alkyl-, hydroxyC1-C6alkyl-, C1-C3alkoxyC1-C3alkoxy-, C1-C6haloalkoxy, C1-C3haloalkoxyC1-C3alkyl-, C3-C6alkenyloxy, C3-C6alkynyloxy, N—C3-C6cycloalkylamino, —C(R6)═NOR6, phenyl, a 3- to 6-membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O, and a 5- or 6-membered heteroaryl, which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, and wherein said phenyl, heterocyclyl or heteroaryl are optionally substituted by 1, 2 or 3 R9 substituents, which may be the same or different.
  • Preferably, when A is substituted on one or more ring carbon atoms, each R8 is independently selected from the group consisting of halogen, nitro, cyano, —NH2, —NHR7, —N(R7)2, —OH, —OR7, —S(O)rR15, —NR6S(O)2R15, —C(O)OR10, —C(O)R15, —C(O)NR16R17, —S(O)2NR16R17, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C3-C6halocycloalkyl, C3-C6cycloalkoxy, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, C1-C3alkoxyC1-C3alkyl-, hydroxyC1-C6alkyl-, C1-C3alkoxyC1-C3alkoxy-, C1-C6haloalkoxy, C1-C3haloalkoxyC1-C3alkyl-, C3-C6alkenyloxy, C3-C6alkynyloxy, N—C3-C6cycloalkylamino, —C(R6)═NOR6, phenyl and a 5- or 6-membered heteroaryl, which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, and wherein said phenyl or heteroaryl are optionally substituted by 1 or 2 R9 substituents, which may be the same or different.
  • More preferably, when A is substituted on one or more ring carbon atoms, each R8 is independently selected from the group consisting of halogen, nitro, cyano, —NH2, —NHR7, —N(R7)2, —OH, —OR7, —S(O)rR15, —NR6S(O)2R15, —C(O)OR10, —C(O)R15, —C(O)NR16R17, —S(O)2NR16R17, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl-, hydroxyC1-C6alkyl-, C1-C3alkoxyC1-C3alkoxy- and C1-C6haloalkoxy.
  • Even more preferably, when A is substituted on one or more ring carbon atoms, each R8 is independently selected from the group consisting of halogen, nitro, cyano, —NH2, —OH, —S(O)rR15, —C(O)OR10, —C(O)R15, —C(O)NR16R17, —S(O)2NR16R17, C1-C6alkyl and C1-C6haloalkyl.
  • Even more preferably still, when A is substituted on one or more ring carbon atoms, each R8 is independently selected from the group consisting of halogen, cyano, —NH2, —OH, —C(O)NR16R17, C1-C6alkyl and C1-C6haloalkyl.
  • Yet even more preferably still, when A is substituted on one or more ring carbon atoms, each R8 is independently selected from the group consisting of halogen, cyano, —NH2, —C(O)NR16R17, C1-C6alkyl and C1-C6haloalkyl.
  • Further more preferably still, each R8 is independently selected from the group consisting of bromo, chloro, fluoro, cyano, —NH2, —C(O)NH2, —C(O)NHMe, —C(O)N(Me)2, methyl and trifluoromethyl.
  • Most preferably, when A is substituted on one or more ring carbon atoms, each R8 is independently selected from the group consisting of bromo, —NH2, —C(O)NHMe, methyl and trifluoromethyl.
  • In one embodiment, when A is substituted on one or more ring carbon atoms, each R8 is independently selected from the group consisting of bromo, cyano, —NH2, —C(O)NHMe, methyl, trifluoromethyl and phenyl (preferably, each R8 is independently selected from the group consisting of —C(O)NHMe, methyl and trifluoromethyl).
  • When A is substituted on a ring nitrogen atom, R8 is selected from the group consisting of —OR7, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C3-C6halocycloalkyl, C3-C6cycloalkoxy, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, C1-C3alkoxyC1-C3alkyl-, hydroxyC1-C6alkyl-, C1-C3alkoxyC1-C3alkoxy-, C1-C6haloalkoxy, C1-C3haloalkoxyC1-C3alkyl-, C3-C6alkenyloxy and C3-C6alkynyloxy. Preferably, R8 is selected from the group consisting of —OR7, C1-C6alkyl and C1-C6haloalkyl. More preferably, each R8 is C1-C6alky or C1-C6haloalkyl. Even more preferably still, R8 is C1-C6alky. Most preferably R8 is methyl.
  • When A is selected from the group consisting of formula A-1 to A-XXXV, R8a (substituted on a ring nitrogen atom) is selected from the group consisting of hydrogen, C1-C6alkyl and C1-C6haloalkyl, and each R8b, R8c and R8d (substituted on a ring carbon atom) are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, —NH2, —S(O)rR15, —C(O)OR10, —C(O)R15, —C(O)NR16R17, —S(O)2NR16R17, C1-C6alkyl and C1-C6haloalkyl. Preferably, R8a is hydrogen or C1-C6alkyl and each R8b, R8c and R8d are independently selected from the group consisting of hydrogen, halogen, cyano, —NH2, —C(O)NR16R17, C1-C6alkyl and C1-C6haloalkyl. More preferably, R8a is hydrogen or methyl and each R8b, R8c and R8d are independently selected from the group consisting of hydrogen, bromo, chloro, fluoro, cyano, —NH2, —C(O)NH2, —C(O)NHMe, —C(O)N(Me)2, methyl and trifluoromethyl. Even more preferably, R8a is hydrogen or methyl and each R8b, R8c and R8d are independently selected from the group consisting of hydrogen, bromo, —NH2, —C(O)NHMe, methyl and trifluoromethyl. Even more preferably still, R8a is hydrogen or methyl and each R8b, R8c and R8d are independently selected from the group consisting of hydrogen, —C(O)NHMe, methyl and trifluoromethyl.
  • When A is selected from the group consisting of formula A-1 to A-XXXII, R8a (substituted on a ring nitrogen atom) is selected from the group consisting of hydrogen, C1-C6alkyl and C1-C6haloalkyl, and each R8b, R8c and R8d (substituted on a ring carbon atom) are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, —NH2, —S(O)rR15, —C(O)OR10, —C(O)R15, —C(O)NR16R17, —S(O)2NR16R17, C1-C6alkyl and C1-C6haloalkyl. Preferably, R8a is hydrogen or C1-C6alkyl and each R8b, R8c and R8d are independently selected from the group consisting of hydrogen, halogen, cyano, —NH2, —C(O)NR16R17, C1-C6alkyl and C1-C6haloalkyl. More preferably, R8a is hydrogen or methyl and each R8b, R8c and R8d are independently selected from the group consisting of hydrogen, bromo, chloro, fluoro, cyano, —NH2, —C(O)NH2, —C(O)NHMe, —C(O)N(Me)2, methyl and trifluoromethyl. Even more preferably, R8a is hydrogen or methyl and each R8b, R8c and R8d are independently selected from the group consisting of hydrogen, bromo, —NH2, —C(O)NHMe, methyl and trifluoromethyl. Even more preferably still, R8a is hydrogen or methyl and each R8b, R8c and R8d are independently selected from the group consisting of hydrogen, —C(O)NHMe, methyl and trifluoromethyl.
  • When A is selected from the group consisting of formula A-1 to A-X, A-XVII, A-XVIII, A-XIX, A-XXIII, A-XXIV and AXXVII, R8a (substituted on a ring nitrogen atom) is selected from the group consisting of hydrogen, C1-C6alkyl and C1-C6haloalkyl, and each R8b, R8c and R8d (substituted on a ring carbon atom) are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, —NH2, —S(O)rR15, —C(O)OR10, —C(O)R15, —C(O)NR16R17, —S(O)2NR16R17, C1-C6alkyl and C1-C6haloalkyl. Preferably, R8a is hydrogen or C1-C6alkyl and each R8b, R8c and R8d are independently selected from the group consisting of hydrogen, halogen, cyano, —NH2, —C(O)NR16R17, C1-C6alkyl and C1-C6haloalkyl. More preferably, R8a is hydrogen or methyl and each R8b, R8c and R8d are independently selected from the group consisting of hydrogen, bromo, chloro, fluoro, cyano, —NH2, —C(O)NH2, —C(O)NHMe, —C(O)N(Me)2, methyl and trifluoromethyl. Even more preferably, R8a is hydrogen or methyl and each R8b, R8c and R8d are independently selected from the group consisting of hydrogen, bromo, —NH2, —C(O)NHMe, methyl and trifluoromethyl. Even more preferably still, R8a is hydrogen or methyl and each R8b, R8c and R8d are independently selected from the group consisting of hydrogen, —C(O)NHMe, methyl and trifluoromethyl.
  • When A is selected from the group consisting of formula A-1 to A-III, each R8b (substituted on a ring carbon atom) is independently selected from the group consisting of hydrogen, halogen, cyano, —NH2, —C(O)NR16R17, C1-C6alkyl and C1-C6haloalkyl. Preferably, each R8b is independently selected from the group consisting of hydrogen, bromo, chloro, fluoro, cyano, —NH2, —C(O)NH2, —C(O)NHMe, —C(O)N(Me)2, methyl and trifluoromethyl. More preferably, each R8b is independently selected from the group consisting of hydrogen, bromo, —NH2, —C(O)NHMe, methyl and trifluoromethyl. Even more preferably, each R8b is independently selected from the group consisting of hydrogen, —C(O)NHMe, methyl and trifluoromethyl.
  • Each R9 is independently selected from the group consisting of halogen, cyano, —OH, —N(R6)2, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl and C1-C4haloalkoxy. Preferably, each R9 is independently selected from the group consisting of halogen, cyano, —N(R6)2, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl and C1-C4haloalkoxy. More preferably, each R9 is independently selected from the group consisting of halogen, C1-C4alkyl, C1-C4alkoxy and C1-C4haloalkyl. Even more preferably, each R9 is independently selected from the group consisting of halogen and C1-C4alkyl.
  • X is selected from the group consisting of C3-C6cycloalkyl, phenyl, a 5- or 6-membered heteroaryl, which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, and a 4- to 6-membered heterocyclyl, which comprises 1, 2 or 3 heteroatoms individually selected from N, O and S, and wherein said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties are optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R9, and wherein the aforementioned CR1R2, Q and Z moieties may be attached at any position of said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties.
  • Preferably, X is selected from the group consisting of phenyl and a 4- to 6-membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O, and wherein said phenyl or heterocyclyl moieties are optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R9, and wherein the aforementioned CR1R2, Q and Z moieties may be attached at any position of said phenyl or heterocyclyl moieties.
  • More preferably, X is a 4- to 6-membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O, and wherein said heterocyclyl moieties is optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R9, and wherein the aforementioned CR1R2, Q and Z moieties may be attached at any position of said heterocyclyl moiety.
  • In one embodiment, X is a 5-membered heterocyclyl, which comprises 1 heteroatom, wherein said heteroatom is N, and wherein the aforementioned CR1R2, Q and Z moieties may be attached at any position of said heterocyclyl moiety. Preferably, X is a 5-membered heterocyclyl, which comprises 1 heteroatom, wherein said heteroatom is N, and wherein the aforementioned CR1R2 and Q moieties are attached adjacent to the N atom and the Z moiety is attached to the N atom.
  • In another embodiment, X is phenyl optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R9, and wherein the aforementioned CR1R2, Q and Z moieties may be attached at any position of said phenyl moiety. Preferably, X is phenyl and the aforementioned CR1R2 and Q moieties are attached in a position para to the Z moiety.
  • n is 0 or 1. Preferably, n is 0.
  • Z is selected from the group consisting of —C(O)OR10, —CH2OH, —CHO, —C(O)NHOR11, —C(O)NHCN, —OC(O)NHOR11, —OC(O)NHCN, —NR6C(O)NHOR11, —NR6C(O)NHCN, —C(O)NHS(O)2R12, —OC(O)NHS(O)2R12, —NR6C(O)NHS(O)2R12, —S(O)2OR10, —OS(O)2OR10, —NR6S(O)2OR10, —NR6S(O)OR10, —NHS(O)2R14, —S(O)OR10, —OS(O)OR10, —S(O)2NHCN, —S(O)2NHC(O)R18, —S(O)2NHS(O)2R12, —OS(O)2NHCN, —OS(O)2NHS(O)2R12, —OS(O)2NHC(O)R18, —NR6S(O)2NHCN, —NR6S(O)2NHC(O)R18, —N(OH)C(O)R15, —ONHC(O)R15, —NR6S(O)2NHS(O)2R12, —P(O)(R13)(OR10), —P(O)H(OR10), —OP(O)(R13)(OR10), —NR6P(O)(R13)(OR10) and tetrazole.
  • Preferably, Z is selected from the group consisting of —C(O)OR10, —C(O)NHOR11, —OC(O)NHOR11, —NR6C(O)NHOR11, —C(O)NHS(O)2R12, —OC(O)NHS(O)2R12, —NR6C(O)NHS(O)2R12, —S(O)2OR10, —OS(O)2OR10, —NR6S(O)2OR10, —NR6S(O)OR10, —NHS(O)2R14, —S(O)OR10, —OS(O)OR10, —S(O)2NHC(O)R18, —S(O)2NHS(O)2R12, —OS(O)2NHS(O)2R12, —OS(O)2NHC(O)R18, —NR6S(O)2NHC(O)R18, —N(OH)C(O)R15, —ONHC(O)R15, —NR6S(O)2NHS(O)2R12, —P(O)(R13)(OR10), —P(O)H(OR10), —OP(O)(R13)(OR10) and —NR6P(O)(R13)(OR10).
  • More preferably, Z is selected from the group consisting of —C(O)OR10, —C(O)NHOR11, —C(O)NHS(O)2R12, —S(O)2OR10, —OS(O)2OR10, —NR6S(O)2OR10, —NHS(O)2R14, —S(O)OR10 and —P(O)(R13)(OR10).
  • Even more preferably Z is selected from the group consisting of —C(O)OR10, —C(O)NHS(O)2R12, —S(O)2OR10, —OS(O)2OR10 and —P(O)(R13)(OR10).
  • Even more preferably still Z is selected from the group consisting of —C(O)OH, —C(O)OCH3, —C(O)OCH2CH3, —C(O)OCH(CH3)2, —C(O)OC(CH3)3, —C(O)OCH2C6H5, —C(O)OC6H5, —C(O)NHS(O)2CH3, —S(O)2OH, —OS(O)2OH, —P(O)(OH)(OH), —P(O)(OH)(OCH2CH3), —P(O)(OH)(OCH3), —P(O)(OCH3)(OCH3), —P(O)(OCH2CH3)(OCH2CH3), —P(O)(CH3)(OH) and —P(O)(CH3)(OCH2CH3).
  • Yet even more preferably still, Z is selected from the group consisting of —C(O)OH, —C(O)OCH3, —C(O)OCH2CH3, —C(O)OC(CH3)3, —C(O)NHS(O)2CH3, —S(O)2OH, —OS(O)2OH, —P(O)(OH)(OH), —P(O)(OH)(OCH2CH3), —P(O)(OH)(OCH3), —P(O)(OCH3)(OCH3), —P(O)(OCH2CH3)(OCH2CH3), —P(O)(CH3)(OH) and —P(O)(CH3)(OCH2CH3).
  • Further more preferably still, Z is selected from the group consisting of —C(O)OH, —C(O)NHS(O)2CH3, —S(O)2OH, —OS(O)2OH, —P(O)(OH)(OH), —P(O)(OH)(OCH2CH3), —P(O)(OH)(OCH3) and —P(O)(CH3)(OH).
  • Most preferably Z is —C(O)OH or —S(O)2OH.
  • In one embodiment Z is selected from the group consisting of —C(O)OR10, —C(O)NHS(O)2R12, —S(O)2OR10, and —P(O)(R13)(OR10) (preferably, —C(O)OH, —C(O)OCH3, —C(O)OCH2CH3, —C(O)NHS(O)2CH3, —S(O)2OH, —P(O)(OH)(OH), —P(O)(OH)(OCH2CH3), —P(O)(CH3)(OH) and —P(O)(CH3)(OCH2CH3)).
  • R10 is selected from the group consisting of hydrogen, C1-C6alkyl, phenyl and benzyl, and wherein said phenyl or benzyl are optionally substituted by 1, 2 or 3 R9 substituents, which may be the same or different. Preferably, R10 is selected from the group consisting of hydrogen, C1-C6alkyl, phenyl and benzyl. More preferably, R10 is selected from the group consisting of hydrogen and C1-C6alkyl. Even more preferably, R10 is selected from the group consisting of hydrogen, methyl, ethyl and tert-butyl. Most preferably, R10 is hydrogen.
  • R11 is selected from the group consisting of hydrogen, C1-C6alkyl and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R9 substituents, which may be the same or different. Preferably, R11 is selected from the group consisting of hydrogen, C1-C6alkyl and phenyl. More preferably, R11 is selected from the group consisting of hydrogen and C1-C6alkyl. Even more preferably, R11 is C1-C6alkyl. Most preferably, R11 is methyl.
  • R12 is selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, —OH, —N(R6)2 and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R9 substituents, which may be the same or different. Preferably, R12 is selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, —OH, —N(R6)2 and phenyl. More preferably, R12 is selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl and —N(R6)2. Even more preferably, R12 is selected from the group consisting of methyl, —N(Me)2 and trifluoromethyl. Most preferably, R12 is methyl.
  • R13 is selected from the group consisting of —OH, C1-C6alkyl, C1-C6alkoxy and phenyl. Preferably R13 is selected from the group consisting of —OH, C1-C6alkyl and C1-C6alkoxy. More preferably, R13 is selected from the group consisting of —OH and C1-C6alkoxy. Even more preferably, R13 is selected from the group consisting of —OH, methoxy and ethoxy. Most preferably, R13 is —OH.
  • R14 is C1-C6haloalkyl. Preferably, R14 is trifluoromethyl.
  • R15 is selected from the group consisting of C1-C6alkyl and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R9 substituents, which may be the same or different. Preferably, R15 is selected from the group consisting of C1-C6alkyl and phenyl. More preferably, R15 is C1-C6alkyl. Most preferably R15 is methyl.
  • R15a is phenyl, wherein said phenyl is optionally substituted by 1, 2 or 3 R9 substituents, which may be the same or different. Preferably, R15a is phenyl optionally substituted by 1 R9 substituent. More preferably, R15a is phenyl.
  • R16 and R17 are independently selected from the group consisting of hydrogen and C1-C6alkyl. Preferably, R16 and R17 are independently selected from the group consisting of hydrogen and methyl.
  • Alternatively, R16 and R17 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S. Preferably, R16 and R17 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N and O. More preferably, R16 and R17 together with the nitrogen atom to which they are attached form an pyrrolidyl, oxazolidinyl, imidazolidinyl, piperidyl, piperazinyl or morpholinyl group.
  • R18 is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, —N(R6)2 and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R9 substituents, which may be the same or different. Preferably, R18 is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, —N(R6)2 and phenyl. More preferably, R18 is selected from the group consisting of hydrogen, C1-C6alkyl and C1-C6haloalkyl. Further more preferably, R18 is selected from the group consisting of C1-C6alkyl and C1-C6haloalkyl. Most preferably, R18 is methyl or trifluoromethyl.
    • r is 0, 1 or 2. Preferably, r is 0 or 2.
  • In a set of preferred embodiments, in a compound according to formula (I) of the invention,
  • R1 is hydrogen or C1-C6alkyl;
    R2 is hydrogen or methyl;
    Q is (CR1aR2b)m;
    m is 0, 1 or 2;
    R1a and R2b are independently selected from the group consisting of hydrogen, C1-C6alkyl, —OH and —NH2;
    R3, R3a, R4 and R5 are independently selected from the group consisting of hydrogen, chloro, fluoro, bromo and methyl;
    each R6 is independently selected from hydrogen and methyl;
    each R7 is C1-C6alkyl;
  • A is a 5-membered heteroaryl attached to the rest of the molecule via a ring carbon atom, which comprises 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S, and wherein the heteroaryl may, where feasible, be optionally substituted by 1, 2 or 3 R8 substituents, which may be the same or different;
  • when A is substituted on one or more ring carbon atoms, each R8 is independently selected from the group consisting of halogen, nitro, cyano, —NH2, —S(O)rR15, —C(O)OR10, —C(O)R15, —C(O)NR16R17, —S(O)2NR16R17, C1-C6alkyl and C1-C6haloalkyl;
    and/or
    when A is substituted on a ring nitrogen atom, R8 is C1-C6alky or C1-C6haloalkyl; and
    n is 0;
    Z is selected from the group consisting of —C(O)OR10, —C(O)NHS(O)2R12, —S(O)2OR10, —OS(O)2OR10 and —P(O)(R13)(OR10);
    R10 is selected from the group consisting of hydrogen, C1-C6alkyl, phenyl and benzyl;
    R12 is selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl and —N(R6)2;
    R13 is selected from the group consisting of —OH, C1-C6alkyl and C1-C6alkoxy;
    R15 is C1-C6alkyl;
    R16 and R17 are independently selected from the group consisting of hydrogen and methyl; and
    r is 0 or 2.
  • More preferably,
  • R1 is hydrogen or methyl;
    R2 is hydrogen or methyl;
    Q is (CR1aR2b)m;
    m is 0 or 1;
    R1a and R2b are independently selected from the group consisting of hydrogen and methyl;
    R3, R3a, R4 and R5 are independently selected from the group consisting of hydrogen, chloro and fluoro; A is a heteroaryl selected from the group consisting of 1,2,4-oxadiazol-5-yl, thiadiazol-5-yl, 1,2,4-thiadiazol-5-yl, thiadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,5-thiadiazol-3-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,5-oxadiazol-3-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, triazol-4-yl, triazol-5-yl, 2-methyltetrazol-5-yl, 1-methyltetrazol-5-yl, thiazol-2-yl, thiazol-4-yl, isothiazol-5-yl, isothiazol-4-yl, isothiazol-3-yl, oxazol-2-yl, oxazol-4-yl, isoxazol-3-yl, isoxazol-5-yl, imidazol-5-yl, imidazol-2-yl, 3-furyl, 2-furyl, 3-thienyl, pyrazol-5-yl, pyrazol-3-yl and 2-thienyl wherein the heteroaryl may, where feasible, be optionally substituted by 1, 2 or 3 R8 substituents, which may be the same or different;
    when A is substituted on one or more ring carbon atoms, each R8 is independently selected from the group consisting of halogen, cyano, —NH2, —C(O)NR16R17, C1-C6alkyl and C1-C6haloalkyl;
    and/or
    when A is substituted on a ring nitrogen atom, R8 is C1-C6alkyl; and
    n is 0;
    Z is selected from the group consisting of —C(O)OH, —C(O)OCH3, —C(O)OCH2CH3, —C(O)OCH(CH3)2, —C(O)OC(CH3)3, —C(O)OCH2C6H5, —C(O)OC6H5, —C(O)NHS(O)2CH3, —S(O)2OH, —OS(O)2OH, —P(O)(OH)(OH), —P(O)(OH)(OCH2CH3), —P(O)(OH)(OCH3), —P(O)(OCH3)(OCH3), —P(O)(OCH2CH3)(OCH2CH3), —P(O)(CH3)(OH) and —P(O)(CH3)(OCH2CH3); and
    R16 and R17 are independently selected from the group consisting of hydrogen and methyl.
  • In a further set of preferred embodiments, the compound according to formula (I) is selected from a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e) or (I-f),
  • Figure US20220104493A1-20220407-C00029
  • wherein in a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e) and (I-f),
    each R8b is independently selected from the group consisting of hydrogen, bromo, chloro, fluoro, cyano, —NH2, —C(O)NH2, —C(O)NHMe, —C(O)N(Me)2, methyl and trifluoromethyl; and
    Z is selected from the group consisting of —C(O)OH, —C(O)OCH3, —C(O)OCH2CH3, —C(O)OC(CH3)3, —C(O)NHS(O)2CH3, —S(O)2OH, —OS(O)2OH, —P(O)(OH)(OH), —P(O)(OH)(OCH2CH3), —P(O)(OH)(OCH3), —P(O)(OCH3)(OCH3), —P(O)(OCH2CH3)(OCH2CH3), —P(O)(CH3)(OH) and —P(O)(CH3)(OCH2CH3).
  • In a further more preferred set of embodiments, the compound according to formula (I) is selected from a compound of formula (I-aa), (I-bb), (I-cc), (I-dd), (I-ee) or (I-ff),
  • Figure US20220104493A1-20220407-C00030
  • wherein in a compound of formula (I-aa), (I-bb), (I-cc), (I-dd), (I-ee) and (I-ff),
    • Z is —C(O)OH or —S(O)2OH.
  • In a another set of preferred embodiments, the compound according to formula (I) is selected from a compound of formula (I-h), (I-k) or (I-m),
  • Figure US20220104493A1-20220407-C00031
  • wherein in a compound of formula (I-h), (I-k) or (I-m),
    R1 is hydrogen or methyl;
    R2 is hydrogen or methyl;
    R3, R3a, R4 and R5 are independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, cyano, methyl and trifluoromethyl;
    each R6 is independently hydrogen or methyl;
    each R8b is independently selected from the group consisting of hydrogen, halogen, cyano, —NH2, —C(O)NR16R17, C1-C6alkyl and C1-C6haloalkyl;
    Z is selected from the group consisting of —C(O)OR10, —C(O)NHS(O)2R12, —S(O)2OR10, and —P(O)(R13)(OR10);
    R10 is selected from the group consisting of hydrogen and C1-C6alkyl;
    R12 is selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl and —N(R6)2;
    R13 is selected from the group consisting of —OH, C1-C6alkyl and C1-C6alkoxy; and
    R16 and R17 are independently selected from the group consisting of hydrogen and methyl.
  • In one set of embodiments, the compound according to formula (I) is selected from a compound A1 to A101 listed in Table A.
  • It should be understood that compounds of formula (I) may exist/be manufactured in ‘procidal form’, wherein they comprise a group ‘G’. Such compounds are referred to herein as compounds of formula (I-IV).
  • G is a group which may be removed in a plant by any appropriate mechanism including, but not limited to, metabolism and chemical degradation to give a compound of formula (I-I), (I-II) or (I-III) wherein Z contains an acidic proton, for example see the scheme below:
  • Figure US20220104493A1-20220407-C00032
  • Whilst such G groups may be considered as ‘procidal’, and thus yield active herbicidal compounds once removed, compounds comprising such groups may also exhibit herbicidal activity in their own right. In such cases in a compound of formula (I-IV), Z-G may include but is not limited to, any one of (G1) to (G7) below and E indicates the point of attachment to the remaining part of a compound of formula (I):
  • Figure US20220104493A1-20220407-C00033
  • In embodiments where Z-G is (G1) to (G7), G, R19, R20, R21, R22 and R23 are defined as follows:
  • G is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, —C(R21R22)OC(O)R19, phenyl or phenyl-C1-C4alkyl-, wherein said phenyl moiety is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, C1-C6alkyl, C1-C6haloalkyl or C1-C6alkoxy.
  • R19 is C1-C6alkyl or phenyl,
    R20 is hydroxy, C1-C6alkyl, C1-C6alkoxy or phenyl,
    R21 is hydrogen or methyl,
    R22 is hydrogen or methyl,
    R23 is hydrogen or C1-C6alkyl.
  • The compounds in Tables 1 to 27 below illustrate the compounds of the invention. The skilled person would understand that the compounds of formula (I) may exist as an agronomically acceptable salt, a zwitterion or an agronomically acceptable salt of a zwitterion as described hereinbefore.
  • TABLE 1
    Com-
    pound
    number R3 R3a R4 R5 Z m Q
    1.001 H H H H —C(O)OH 0 —
    1.002 H H H H —C(O)OMe 0 —
    1.003 H H H H —C(O)NHOMe 0 —
    1.004 H H H H —OC(O)NHOMe 0 —
    1.005 H H H H —NHC(O)NHOMe 0 —
    1.006 H H H H —NMeC(O)NHOMe 0 —
    1.007 H H H H —C(O)NHS(O)2Me 0 —
    1.008 H H H H —OC(O)NHS(O)2Me 0 —
    1.009 H H H H —NHC(O)NHS(O)2Me 0 —
    1.010 H H H H —NMeC(O)NHS(O)2Me 0 —
    1.011 H H H H —S(O)2OH 0 —
    1.012 H H H H —OS(O)2OH 0 —
    1.013 H H H H —NHS(O)2OH 0 —
    1.014 H H H H —NMeS(O)2OH 0 —
    1.015 H H H H —S(O)OH 0 —
    1.016 H H H H —OS(O)OH 0 —
    1.017 H H H H —NHS(O)OH 0 —
    1.018 H H H H —NMeS(O)OH 0 —
    1.019 H H H H —NHS(O)2CF3 0 —
    1.020 H H H H —S(O)2NHC(O)Me 0 —
    1.021 H H H H —OS(O)2NHC(O)Me 0 —
    1.022 H H H H —NHS(O)2NHC(O)Me 0 —
    1.023 H H H H —NMeS(O)2NHC(O)Me 0 —
    1.024 H H H H —P(O)(OH)(OMe) 0 —
    1.025 H H H H —P(O)(OH)(OH) 0 —
    1.026 H H H H —OP(O)(OH)(OMe) 0 —
    1.027 H H H H —OP(O)(OH)(OH) 0 —
    1.028 H H H H —NHP(O)(OH)(OMe) 0 —
    1.029 H H H H —NHP(O)(OH)(OH) 0 —
    1.030 H H H H —NMeP(O)(OH)(OMe) 0 —
    1.031 H H H H —NMeP(O)(OH)(OH) 0 —
    1.032 H H H H —tetrazole 0 —
    1.033 H H H H —S(O)2OH 1 CH(NH2)
    1.033 H H H H —C(O)OH 1 CH(NH2)
    1.035 H H H H —S(O)2OH 2 CH(OH)CH2
    1.036 H H H H —C(O)OH 2 CH(OH)CH2
    1.037 H H H H —S(O)2OH 1 CH(OH)
    1.038 H H H H —C(O)OH 1 CH(OH)
    1.039 H H H H —C(O)NHCN 0 —
    1.040 H H H H —OC(O)NHCN 0 —
    1.041 H H H H —NHC(O)NHCN 0 —
    1.042 H H H H —NMeC(O)NHCN 0 —
    1.043 H H H H —S(O)2NHCN 0 —
    1.044 H H H H —OS(O)2NHCN 0 —
    1.045 H H H H —NHS(O)2NHCN 0 —
    1.046 H H H H —NMeS(O)2NHCN 0 —
    1.047 H H H H —S(O)2NHS(O)2Me 0 —
    1.048 H H H H —OS(O)2NHS(O)2Me 0 —
    1.049 H H H H —NHS(O)2NHS(O)2Me 0 —
    1.050 H H H H —NMeS(O)2NHS(O)2Me 0 —
    1.051 H H H H —P(O)H(OH) 0 —
    1.052 H H H H —N(OH)C(O)Me 0 —
    1.053 H H H H —ONHC(O)Me 0 —
  • This table discloses 53 specific compounds (1.001 to 1.053) of the formula (T-1):
  • Figure US20220104493A1-20220407-C00034
  • Wherein m, Q, R3, R3a, R4, R5 and Z are as defined in Table 1, R1 and R2 are hydrogen and n is 0.
  • This table discloses 49 specific compounds 2.001 to 2.049) of the formula (T-2):
  • Figure US20220104493A1-20220407-C00035
  • Wherein m, Q, R3, R3a, R4, R5 and Z are as defined in Table 2, R1 and R2 are hydrogen and n is 0.
  • TABLE 2
    Com-
    pound
    number R3 R3a R4 R5 Z m Q
    2.001 H H H H —C(O)OH 1 CH2
    2.002 H H H H —C(O)OMe 1 CH2
    2.003 H H H H —C(O)NHOMe 1 CH2
    2.004 H H H H —OC(O)NHOMe 1 CH2
    2.005 H H H H —NHC(O)NHOMe 1 CH2
    2.006 H H H H —NMeC(O)NHOMe 1 CH2
    2.007 H H H H —C(O)NHS(O)2Me 1 CH2
    2.008 H H H H —OC(O)NHS(O)2Me 1 CH2
    2.009 H H H H —NHC(O)NHS(O)2Me 1 CH2
    2.010 H H H H —NMeC(O)NHS(O)2Me 1 CH2
    2.011 H H H H —S(O)2OH 1 CH2
    2.012 H H H H —OS(O)2OH 1 CH2
    2.013 H H H H —NHS(O)2OH 1 CH2
    2.014 H H H H —NMeS(O)2OH 1 CH2
    2.015 H H H H —S(O)OH 1 CH2
    2.016 H H H H —OS(O)OH 1 CH2
    2.017 H H H H —NHS(O)OH 1 CH2
    2.018 H H H H —NMeS(O)OH 1 CH2
    2.019 H H H H —NHS(O)2CF3 1 CH2
    2.020 H H H H —S(O)2NHC(O)Me 1 CH2
    2.021 H H H H —OS(O)2NHC(O)Me 1 CH2
    2.022 H H H H —NHS(O)2NHC(O)Me 1 CH2
    2.023 H H H H —NMeS(O)2NHC(O)Me 1 CH2
    2.024 H H H H —P(O)(OH)(OMe) 1 CH2
    2.025 H H H H —P(O)(OH)(OH) 1 CH2
    2.026 H H H H —OP(O)(OH)(OMe) 1 CH2
    2.027 H H H H —OP(O)(OH)(OH) 1 CH2
    2.028 H H H H —NHP(O)(OH)(OMe) 1 CH2
    2.029 H H H H —NHP(O)(OH)(OH) 1 CH2
    2.030 H H H H —NMeP(O)(OH)(OMe) 1 CH2
    2.031 H H H H —NMeP(O)(OH)(OH) 1 CH2
    2.032 H H H H —tetrazole 1 CH2
    2.033 H H H H —S(O)2OH 2 CH2CH(NH2)
    2.034 H H H H —C(O)OH 2 CH2CH(NH2)
    2.035 H H H H —C(O)NHCN 1 CH2
    2.036 H H H H —OC(O)NHCN 1 CH2
    2.037 H H H H —NHC(O)NHCN 1 CH2
    2.038 H H H H —NMeC(O)NHCN 1 CH2
    2.039 H H H H —S(O)2NHCN 1 CH2
    2.040 H H H H —OS(O)2NHCN 1 CH2
    2.041 H H H H —NHS(O)2NHCN 1 CH2
    2.042 H H H H —NMeS(O)2NHCN 1 CH2
    2.043 H H H H —S(O)2NHS(O)2Me 1 CH2
    2.044 H H H H —OS(O)2NHS(O)2Me 1 CH2
    2.045 H H H H —NHS(O)2NHS(O)2Me 1 CH2
    2.046 H H H H —NMeS(O)2NHS(O)2Me 1 CH2
    2.047 H H H H —P(O)H(OH) 1 CH2
    2.048 H H H H —N(OH)C(O)Me 1 CH2
    2.049 H H H H —ONHC(O)Me 1 CH2
  • TABLE 3
    Compound
    number R3 R3a R4 R5 Z m Q
    3.001 H H H H —C(O)OH 2 CH2CH2
    3.002 H H H H —C(O)OMe 2 CH2CH2
    3.003 H H H H —C(O)NHOMe 2 CH2CH2
    3.004 H H H H —OC(O)NHOMe 2 CH2CH2
    3.005 H H H H —NHC(O)NHOMe 2 CH2CH2
    3.006 H H H H —NMeC(O)NHOMe 2 CH2CH2
    3.007 H H H H —C(O)NHS(O)2Me 2 CH2CH2
    3.008 H H H H —OC(O)NHS(O)2Me 2 CH2CH2
    3.009 H H H H —NHC(O)NHS(O)2Me 2 CH2CH2
    3.010 H H H H —NMeC(O)NHS(O)2Me 2 CH2CH2
    3.011 H H H H —S(O)2OH 2 CH2CH2
    3.012 H H H H —OS(O)2OH 2 CH2CH2
    3.013 H H H H —NHS(O)2OH 2 CH2CH2
    3.014 H H H H —NMeS(O)2OH 2 CH2CH2
    3.015 H H H H —S(O)OH 2 CH2CH2
    3.016 H H H H —OS(O)OH 2 CH2CH2
    3.017 H H H H —NHS(O)OH 2 CH2CH2
    3.018 H H H H —NMeS(O)OH 2 CH2CH2
    3.019 H H H H —NHS(O)2CF3 2 CH2CH2
    3.020 H H H H —S(O)2NHC(O)Me 2 CH2CH2
    3.021 H H H H —OS(O)2NHC(O)Me 2 CH2CH2
    3.022 H H H H —NHS(O)2NHC(O)Me 2 CH2CH2
    3.023 H H H H —NMeS(O)2NHC(O)Me 2 CH2CH2
    3.024 H H H H —P(O)(OH)(OMe) 2 CH2CH2
    3.025 H H H H —P(O)(OH)(OH) 2 CH2CH2
    3.026 H H H H —OP(O)(OH)(OMe) 2 CH2CH2
    3.027 H H H H —OP(O)(OH)(OH) 2 CH2CH2
    3.028 H H H H —NHP(O)(OH)(OMe) 2 CH2CH2
    3.029 H H H H —NHP(O)(OH)(OH) 2 CH2CH2
    3.030 H H H H —NMeP(O)(OH)(OMe) 2 CH2CH2
    3.031 H H H H —NMeP(O)(OH)(OH) 2 CH2CH2
    3.032 H H H H —tetrazole 2 CH2CH2
    3.033 H H H H —S(O)2OH 3 CH2CH2CH(NH2)
    3.034 H H H H —C(O)OH 3 CH2CH2CH(NH2)
    3.035 H H H H —C(O)NHCN 2 CH2CH2
    3.036 H H H H —OC(O)NHCN 2 CH2CH2
    3.037 H H H H —NHC(O)NHCN 2 CH2CH2
    3.038 H H H H —NMeC(O)NHCN 2 CH2CH2
    3.039 H H H H —S(O)2NHCN 2 CH2CH2
    3.040 H H H H —OS(O)2NHCN 2 CH2CH2
    3.041 H H H H —NHS(O)2NHCN 2 CH2CH2
    3.042 H H H H —NMeS(O)2NHCN 2 CH2CH2
    3.043 H H H H —S(O)2NHS(O)2Me 2 CH2CH2
    3.044 H H H H —OS(O)2NHS(O)2Me 2 CH2CH2
    3.045 H H H H —NHS(O)2NHS(O)2Me 2 CH2CH2
    3.046 H H H H —NMeS(O)2NHS(O)2Me 2 CH2CH2
    3.047 H H H H —P(O)H(OH) 2 CH2CH2
    3.048 H H H H —N(OH)C(O)Me 2 CH2CH2
    3.049 H H H H —ONHC(O)Me 2 CH2CH2
  • This table discloses 49 specific compounds (3.001 to 3.049) of the formula (T-3):
  • Figure US20220104493A1-20220407-C00036
  • wherein m, Q, R3, R3a, R4, R5 and Z are as defined in Table 3, R1 and R2 are hydrogen and n is 0.
    • Table 4:
  • This table discloses 53 specific compounds (4.001 to 4.053) of the formula (T-4):
  • Figure US20220104493A1-20220407-C00037
  • wherein m, Q, R3, R3a, R4, R5 and Z are as defined above in Table 1, R1 and R2 are hydrogen and n is 0.
    • Table 5:
  • This table discloses 49 specific compounds (5.001 to 5.049) of the formula (T-5):
  • Figure US20220104493A1-20220407-C00038
  • wherein m, Q, R3, R3a, R4, R5 and Z are as defined above in Table 2, R1 and R2 are hydrogen and n is 0.
    • Table 6:
  • This table discloses 49 specific compounds (6.001 to 6.049) of the formula (T-6):
  • Figure US20220104493A1-20220407-C00039
  • wherein m, Q, R3, R31, R4, R5 and Z are as defined above in Table 3, R1 and R2 are hydrogen and n is 0.
    • Table 7:
  • This table discloses 53 specific compounds (7.001 to 7.053) of the formula (T-7):
  • Figure US20220104493A1-20220407-C00040
  • wherein m, Q, R3, R3a, R4, R5 and Z are as defined above in Table 1, R1 and R2 are hydrogen and n is 0.
    • Table 8:
  • This table discloses 49 specific compounds (8.001 to 8.049) of the formula (T-8):
  • Figure US20220104493A1-20220407-C00041
  • wherein m, Q, R3, R3a, R4, R5 and Z are as defined above in Table 2, R1 and R2 are hydrogen and n is 0.
    • Table 9:
  • This table discloses 49 specific compounds (9.001 to 9.049) of the formula (T-9):
  • Figure US20220104493A1-20220407-C00042
  • wherein m, Q, R3, R31, R4, R5 and Z are as defined above in Table 3, R1 and R2 are hydrogen and n is 0.
    • Table 10:
  • This table discloses 53 specific compounds (10.001 to 10.053) of the formula (T-10):
  • Figure US20220104493A1-20220407-C00043
  • wherein m, Q, R3, R3a, R4, R5 and Z are as defined above in Table 1, R1 and R2 are hydrogen and n is 0.
    • Table 11:
  • This table discloses 49 specific compounds (11.001 to 11.049) of the formula (T-11):
  • Figure US20220104493A1-20220407-C00044
  • wherein m, Q, R3, R3a, R4, R5 and Z are as defined above in Table 2, R1 and R2 are hydrogen and n is 0.
    • Table 12:
  • This table discloses 49 specific compounds (12.001 to 12.049) of the formula (T-12):
  • Figure US20220104493A1-20220407-C00045
  • wherein m, Q, R3, R31, R4, R5 and Z are as defined above in Table 3, R1 and R2 are hydrogen and n is 0.
    • Table 13:
  • This table discloses 53 specific compounds (13.001 to 13.053) of the formula (T-13):
  • Figure US20220104493A1-20220407-C00046
  • wherein m, Q, R3, R3a, R4, R5 and Z are as defined above in Table 1, R1 and R2 are hydrogen and n is 0.
    • Table 14:
  • This table discloses 49 specific compounds (14.001 to 14.049) of the formula (T-14):
  • Figure US20220104493A1-20220407-C00047
  • wherein m, Q, R3, R3a, R4, R5 and Z are as defined above in Table 2, R1 and R2 are hydrogen and n is 0.
    • Table 15:
  • This table discloses 49 specific compounds (15.001 to 15.049) of the formula (T-15):
  • Figure US20220104493A1-20220407-C00048
  • wherein m, Q, R3, R3a, R4, R5 and Z are as defined above in Table 3, R1 and R2 are hydrogen and n is 0.
    • Table 16:
  • This table discloses 53 specific compounds (16.001 to 16.053) of the formula (T-16):
  • Figure US20220104493A1-20220407-C00049
  • wherein m, Q, R3, R3a, R4, R5 and Z are as defined above in Table 1, R1 and R2 are hydrogen and n is 0.
    • Table 17:
  • This table discloses 49 specific compounds (17.001 to 17.049) of the formula (T-17):
  • Figure US20220104493A1-20220407-C00050
  • wherein m, Q, R3, R3a, R4, R5 and Z are as defined above in Table 2, R1 and R2 are hydrogen and n is 0.
    • Table 18:
  • This table discloses 49 specific compounds (18.001 to 18.049) of the formula (T-18):
  • Figure US20220104493A1-20220407-C00051
  • wherein m, Q, R3, R3a, R4, R5 and Z are as defined above in Table 3, R1 and R2 are hydrogen and n is 0.
    • Table 19:
  • This table discloses 53 specific compounds (19.001 to 19.053) of the formula (T-19):
  • Figure US20220104493A1-20220407-C00052
  • wherein m, Q, R3, R3a, R4, R5 and Z are as defined above in Table 1, R1 and R2 are hydrogen and n is 0.
    • Table 20:
  • This table discloses 49 specific compounds (20.001 to 20.049) of the formula (T-20):
  • Figure US20220104493A1-20220407-C00053
  • wherein m, Q, R3, R31, R4, R5 and Z are as defined above in Table 2, R1 and R2 are hydrogen and n is 0.
    • Table 21:
  • This table discloses 49 specific compounds (21.001 to 21.049) of the formula (T-21):
  • Figure US20220104493A1-20220407-C00054
  • wherein m, Q, R3, R3a, R4, R5 and Z are as defined above in Table 3, R1 and R2 are hydrogen and n is 0.
    • Table 22:
  • This table discloses 53 specific compounds (22.001 to 22.053) of the formula (T-22):
  • Figure US20220104493A1-20220407-C00055
  • wherein m, Q, R3, R3a, R4, R5 and Z are as defined above in Table 1, R1 and R2 are hydrogen and n is 0.
    • Table 23:
  • This table discloses 49 specific compounds (23.001 to 23.049) of the formula (T-23):
  • Figure US20220104493A1-20220407-C00056
  • wherein m, Q, R3, R3a, R4, R5 and Z are as defined above in Table 2, R1 and R2 are hydrogen and n is 0.
    • Table 24:
  • This table discloses 49 specific compounds (24.001 to 24.049) of the formula (T-24):
  • Figure US20220104493A1-20220407-C00057
  • wherein m, Q, R3, R3a, R4, R5 and Z are as defined above in Table 3, R1 and R2 are hydrogen and n is 0.
    • Table 25:
  • This table discloses 53 specific compounds (25.001 to 25.053) of the formula (T-25):
  • Figure US20220104493A1-20220407-C00058
  • wherein m, Q, R3, R3a, R4, R5 and Z are as defined above in Table 1, R1 and R2 are hydrogen and n is 0.
    • Table 26:
  • This table discloses 49 specific compounds (26.001 to 26.049) of the formula (T-26):
  • Figure US20220104493A1-20220407-C00059
  • wherein m, Q, R3, R3a, R4, R5 and Z are as defined above in Table 2, R1 and R2 are hydrogen and n is 0.
    • Table 27:
  • This table discloses 49 specific compounds (27.001 to 27.049) of the formula (T-27):
  • Figure US20220104493A1-20220407-C00060
  • wherein m, Q, R3, R3a, R4, R5 and Z are as defined above in Table 3, R1 and R2 are hydrogen and n is 0.
  • The compounds of the present invention may be prepared according to the following schemes in which the substituents n, m, r, A, Q, X, Z, R1, R2, R1a, R2b, R2, R3, R3a, R4, R5, R6, R7, R7a, R7b, R7c, R8, R9, R10, R11, R12, R13, R14, R15, R15a, R16, R17 and R18 are as defined hereinbefore unless explicitly stated otherwise. The compounds of the preceeding Tables 1 to 27 may thus be obtained in an analogous manner.
  • The compounds of formula (I) may be prepared by the alkylation of compounds of formula (X), wherein R3, R3a, R4, R5 and A are as defined for compounds of formula (I), with a suitable alkylating agent of formula (W), wherein R1, R2, Q, X, n and Z are as defined for compounds of formula (I) and LG is a suitable leaving group, for example, halide or pseudohalide such as triflate, mesylate or tosylate, in a suitable solvent at a suitable temperature, as described in reaction scheme 1. Example conditions include stirring a compound of formula (X) with an alkylating agent of formula (W) in a solvent, or mixture of solvents, such as acetone, dichloromethane, dichloroethane, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, water, acetic acid or trifluroacetic acid at a temperature between −78° C. and 150° C. An alkylating agent of formula (W) may include, but is not limited to, bromoacetic acid, methyl bromoacetate, 3-bromopropionoic acid, methyl 3-bromopropionate, 2-bromo-N-methoxyacetamide, sodium 2-bromoethanesulphonate, 2,2-dimethylpropyl 2-(trifluoromethylsulfonyloxy)ethanesulfonate, 2-bromo-N-methanesulfonylacetamide, 3-bromo-N-methanesulfonylpropanamide, dimethoxyphosphorylmethyl trifluoromethanesulfonate, dimethyl 3-bromopropylphosphonate, 3-chloro-2,2-dimethyl-propanoic acid and diethyl 2-bromoethylphosphonate. Such alkylating agents and related compounds are either known in the literature or may be prepared by known literature methods. Compounds of formula (I) which may be described as esters of N-alkyl acids, which include, but are not limited to, esters of carboxylic acids, phosphonic acids, phosphinic acids, sulfonic acids and sulfinic acids, may be subsequently partially or fully hydrolysed by treament with a suitable reagent, for example, aqueous hydrochloric acid or trimethylsilyl bromide, in a suitable solvent at a suitable temperature between 0° C. and 100° C.
  • Figure US20220104493A1-20220407-C00061
  • Additionally, compounds of formula (I) may be prepared by reacting compounds of formula (X), wherein R3, R3a, R4, R5 and A are as defined for compounds of formula (I), with a suitably activated electrophilic alkene of formula (B), wherein Z is —S(O)2OR10, —P(O)(R13)(OR10) or —C(O)OR10 and R1, R2, R1a, R10 and R13 are as defined for compounds of formula (I), in a suitable solvent at a suitable temperature. Compounds of formula (B) are known in the literature, or may be prepared by known methods. Example reagents include, but are not limited to, acrylic acid, methacrylic acid, crotonic acid, 3,3-dimethylacrylic acid, methyl acrylate, ethene sulfonic acid, isopropyl ethylenesulfonate, 2,2-dimethylpropyl ethenesulfonate and dimethyl vinylphosphonate. The direct products of these reactions, which may be described as esters of N-alkyl acids, which include, but are not limited to, esters of carboxylic acids, phosphonic acids, phosphinic acids, sulfonic acids and sulfinic acids, may be subsequently partially or fully hydrolysed by treament with a suitable reagent in a suitable solvent at a suitable temperature, as described in reaction scheme 2.
  • Figure US20220104493A1-20220407-C00062
  • In a related reaction compounds of formula (I), wherein Q is C(R1aR2b), m is 1, 2 or 3, n=0 and Z is —S(O)2OH, —OS(O)2OH or —NR6S(O)2OH, may be prepared by the reaction of compounds of formula (X), wherein R3, R3a, R4, R5 and A are as defined for compounds of formula (I), with a cyclic alkylating agent of formula (E), (F) or (AF), wherein Ya is C(R1aR2b), 0 or NR6 and R1, R2, Ria and R2b are as defined for compounds of formula (I), in a suitable solvent at a suitable temperature, as described in reaction scheme 3. Suitable solvents and suitable temperatures are as previously described. An alkylating agent of formula (E) or (F) may include, but is not limited to, 1,3-propanesultone, 1,4-butanesultone, ethylenesulfate, 1,3-propylene sulfate and 1,2,3-oxathiazolidine 2,2-dioxide. Such alkylating agents and related compounds are either known in the literature or may be prepared by known literature methods.
  • Figure US20220104493A1-20220407-C00063
  • A compound of formula (I), wherein m is 0, n is 0 and Z is —S(O)2OH, may be prepared from a compound of formula (I), wherein m is 0, n is 0 and Z is C(O)OR10, by treatment with trimethylsilylchlorosulfonate in a suitable solvent at a suitable temperature, as described in reaction scheme 4. Preferred conditions include heating the carboxylate precursor in neat trimethylsilylchlorosulfonate at a temperature between 25° C. and 150° C.
  • Figure US20220104493A1-20220407-C00064
  • Furthermore, compounds of formula (I) may be prepared by reacting compounds of formula (X), wherein R3, R3a, R4, R5 and A are as defined for compounds of formula (I), with a suitable alcohol of formula (WV), wherein R1, R2, Q, X, n and Z are as defined for compounds of formula (I), under Mitsunobu-type conditions such as those reported by Petit et al, Tet. Lett. 2008, 49 (22), 3663. Suitable phosphines include triphenylphosphine, suitable azodicarboxylates include diisopropylazodicarboxylate and suitable acids include fluoroboric acid, triflic acid and bis(trifluoromethylsulfonyl)amine, as described in reaction scheme 5. Such alcohols are either known in the literature or may be prepared by known literature methods.
  • Figure US20220104493A1-20220407-C00065
  • In another approach a compound of formula (I), wherein n, Q, Z, X, R1, R2, R3, R3a, R4, R5 and A are as defined for compounds of formula (I), may be prepared from a compound of formula (R) and an oxidant, in a suitable solvent at a suitable temperature, as outlined in reaction scheme 6. Example oxidants include, but are not limited to, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, tetrachloro-p-benzoquinone, potassium permanganate, manganese dioxide, 2,2,6,6-tetramethyl-1-piperidinyloxy and bromine. Related reactions are known in the literature.
  • Figure US20220104493A1-20220407-C00066
  • A compound of formula (R), wherein n, Q, Z, X, R1, R2, R3, R3a, R4, R5 and A are as defined for compounds of formula (I), may be prepared from a compound of formula (S) and an organometallic of formula (T), wherein M′ includes, but is not limited to, organomagnesium, organolithium, organocopper and organozinc reagents, in a suitable solvent at a suitable temperature, optionally in the presence of an additional transition metal additive, as outlined in reaction scheme 7. Example conditions include treating a compound of formula (S) with a Grignard of formula (T), in the presence of 0.05-100 mol % copper iodide, in a solvent such as tetrahydrofuran at a temperature between −78° C. and 100° C. Organometallics of formula (T) are known in the literature, or may be prepared by known literature methods. Compounds of formula (S) may be prepared by analogous reactions to those for the preparation of compounds of formula (I) from a compound of formula (XX).
  • Figure US20220104493A1-20220407-C00067
  • Biaryl pyridines of formula (X) are known in the literature or may be prepared using literature methods. Example methods include, but are not limited to, the transition metal cross-coupling of compounds of formula (H) and formula (J), or alternatively compounds of formula (K) and formula (L), in which compounds of formula (J) and formula (L), wherein M′ is either an organostannane, organoboronic acid or ester, organotrifluoroborate, organomagnesium, organocopper or organozinc, as outlined in reaction scheme 8. Hal is defined as a halogen or pseudo halogen, for example triflate, mesylate and tosylate. Such cross-couplings include Stille (for example Sauer, J.; Heldmann, D. K. Tetrahedron, 1998, 4297), Suzuki-Miyaura (for example Luebbers, T.; Flohr, A.; Jolidon, S.; David-Pierson, P.; Jacobsen, H.; Ozmen, L.; Baumann, K. Bioorg. Med. Chem. Lett., 2011, 6554), Negishi (for example Imahori, T.; Suzawa, K.; Kondo, Y. Heterocycles, 2008, 1057), and Kumada (for example Heravi, M. M.; Hajiabbasi, P. Monatsh. Chem., 2012, 1575). The coupling partners may be selected with reference to the specific cross-coupling reaction and target product. Transition metal catalysts, ligands, bases, solvents and temperatures may be selected with reference to the desired cross-coupling and are known in the literature. Compounds of formula (H), formula (K) and formula (L) are known in the literature, or may be prepared by known literature methods.
  • Figure US20220104493A1-20220407-C00068
  • A compound of formula (J), wherein M′ is either an organostannane, organoboronic acid or ester, organotrifluoroborate, organomagnesium, organocopper or organozinc, may be prepared from a compound of formula (XX), wherein R3, R3a, R4 and R5 are as defined for compounds of formula (I), by metalation, as outlined in reaction scheme 9. Similar reactions are known in the literature (for example Ramphal et al, WO2015/153683, Unsinn et al., Organic Letters, 15(5), 1128-1131; 2013, Sadler et al., Organic & Biomolecular Chemistry, 12(37), 7318-7327; 2014. Alternatively, an organometallic of formula (J) may be prepared from compounds of formula (K), wherein R3, R3a, R4 and R5 are as defined for compounds of formula (I), and Hal is defined as a halogen or pseudo halogen, for example triflate, mesylate and tosylate, as described in scheme 9. Example conditions to prepare an compound of formula (J) wherein M′ is an organostannane, include treatment of a compound of formula (K) with lithium tributyl tin in an appropriate solvent at an appropriate temperature (for example see WO 2010/038465). Example conditions to prepare compound of formula (J) wherein M′ is an organoboronic acid or ester, include treatment of a compound of formula (K) with bis(pinacolato)diboron, in the presence of an appropriate transition metal catalyst, appropriate ligand, appropriate base, in an appropriate solvent at an appropriate temperature (for example KR 2015135626). Compounds of formula (K) and formula (XX) are either known in the literature or can be prepared by known methods.
  • Figure US20220104493A1-20220407-C00069
  • In an additional approach, outlined in scheme 10, biaryl pyridines of formula (X) may be prepared by classical ring synthesis approaches starting from a compound of formula (ZZ), wherein R3, R3a, R4 and R5 are as defined for compounds of formula (I) and T is a functional group which can be converted through one or more chemical steps into a 5-membered heteroaryl A, wherein A is as defined for compounds of formula (I). Such functional groups include, but are not limited to, acid, ester, nitrile, amide, thioamide and ketone. Related transformations are known in the literature. Substituted pyridines may be prepared using methodology outlined in the literature.
  • Figure US20220104493A1-20220407-C00070
  • The compounds according to the invention can be used as herbicidal agents in unmodified form, but they are generally formulated into compositions in various ways using formulation adjuvants, such as carriers, solvents and surface-active substances. The formulations can be in various physical forms, e.g. in the form of dusting powders, gels, wettable powders, water-dispersible granules, water-dispersible tablets, effervescent pellets, emulsifiable concentrates, microemulsifiable concentrates, oil-in-water emulsions, oil-flowables, aqueous dispersions, oily dispersions, suspo-emulsions, capsule suspensions, emulsifiable granules, soluble liquids, water-soluble concentrates (with water or a water-miscible organic solvent as carrier), impregnated polymer films or in other forms known e.g. from the Manual on Development and Use of FAO and WHO Specifications for Pesticides, United Nations, First Edition, Second Revision (2010). Such formulations can either be used directly or diluted prior to use. The dilutions can be made, for example, with water, liquid fertilisers, micronutrients, biological organisms, oil or solvents.
  • The formulations can be prepared e.g. by mixing the active ingredient with the formulation adjuvants in order to obtain compositions in the form of finely divided solids, granules, solutions, dispersions or emulsions. The active ingredients can also be formulated with other adjuvants, such as finely divided solids, mineral oils, oils of vegetable or animal origin, modified oils of vegetable or animal origin, organic solvents, water, surface-active substances or combinations thereof.
  • The active ingredients can also be contained in very fine microcapsules. Microcapsules contain the active ingredients in a porous carrier. This enables the active ingredients to be released into the environment in controlled amounts (e.g. slow-release). Microcapsules usually have a diameter of from 0.1 to 500 microns. They contain active ingredients in an amount of about from 25 to 95% by weight of the capsule weight. The active ingredients can be in the form of a monolithic solid, in the form of fine particles in solid or liquid dispersion or in the form of a suitable solution. The encapsulating membranes can comprise, for example, natural or synthetic rubbers, cellulose, styrene/butadiene copolymers, polyacrylonitrile, polyacrylate, polyesters, polyamides, polyureas, polyurethane or chemically modified polymers and starch xanthates or other polymers that are known to the person skilled in the art. Alternatively, very fine microcapsules can be formed in which the active ingredient is contained in the form of finely divided particles in a solid matrix of base substance, but the microcapsules are not themselves encapsulated.
  • The formulation adjuvants that are suitable for the preparation of the compositions according to the invention are known per se. As liquid carriers there may be used: water, toluene, xylene, petroleum ether, vegetable oils, acetone, methyl ethyl ketone, cyclohexanone, acid anhydrides, acetonitrile, acetophenone, amyl acetate, 2-butanone, butylene carbonate, chlorobenzene, cyclohexane, cyclohexanol, alkyl esters of acetic acid, diacetone alcohol, 1,2-dichloropropane, diethanolamine, p-diethylbenzene, diethylene glycol, diethylene glycol abietate, diethylene glycol butyl ether, diethylene glycol ethyl ether, diethylene glycol methyl ether, N,N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, dipropylene glycol, dipropylene glycol methyl ether, dipropylene glycol dibenzoate, diproxitol, alkylpyrrolidone, ethyl acetate, 2-ethylhexanol, ethylene carbonate, 1,1,1-trichloroethane, 2-heptanone, alpha-pinene, d-limonene, ethyl lactate, ethylene glycol, ethylene glycol butyl ether, ethylene glycol methyl ether, gamma-butyrolactone, glycerol, glycerol acetate, glycerol diacetate, glycerol triacetate, hexadecane, hexylene glycol, isoamyl acetate, isobornyl acetate, isooctane, isophorone, isopropylbenzene, isopropyl myristate, lactic acid, laurylamine, mesityl oxide, methoxypropanol, methyl isoamyl ketone, methyl isobutyl ketone, methyl laurate, methyl octanoate, methyl oleate, methylene chloride, m-xylene, n-hexane, n-octylamine, octadecanoic acid, octylamine acetate, oleic acid, oleylamine, o-xylene, phenol, polyethylene glycol, propionic acid, propyl lactate, propylene carbonate, propylene glycol, propylene glycol methyl ether, p-xylene, toluene, triethyl phosphate, triethylene glycol, xylenesulfonic acid, paraffin, mineral oil, trichloroethylene, perchloroethylene, ethyl acetate, amyl acetate, butyl acetate, propylene glycol methyl ether, diethylene glycol methyl ether, methanol, ethanol, isopropanol, and alcohols of higher molecular weight, such as amyl alcohol, tetrahydrofurfuryl alcohol, hexanol, octanol, ethylene glycol, propylene glycol, glycerol, N-methyl-2-pyrrolidone and the like.
  • Suitable solid carriers are, for example, talc, titanium dioxide, pyrophyllite clay, silica, attapulgite clay, kieselguhr, limestone, calcium carbonate, bentonite, calcium montmorillonite, cottonseed husks, wheat flour, soybean flour, pumice, wood flour, ground walnut shells, lignin and similar substances.
  • A large number of surface-active substances can advantageously be used in both solid and liquid formulations, especially in those formulations which can be diluted with a carrier prior to use. Surface-active substances may be anionic, cationic, non-ionic or polymeric and they can be used as emulsifiers, wetting agents or suspending agents or for other purposes. Typical surface-active substances include, for example, salts of alkyl sulfates, such as diethanolammonium lauryl sulfate; salts of alkylarylsulfonates, such as calcium dodecylbenzenesulfonate; alkylphenol/alkylene oxide addition products, such as nonylphenol ethoxylate; alcohol/alkylene oxide addition products, such as tridecylalcohol ethoxylate; soaps, such as sodium stearate; salts of alkylnaphthalenesulfonates, such as sodium dibutylnaphthalenesulfonate; dialkyl esters of sulfosuccinate salts, such as sodium di(2-ethylhexyl)sulfosuccinate; sorbitol esters, such as sorbitol oleate; quaternary amines, such as lauryltrimethylammonium chloride, polyethylene glycol esters of fatty acids, such as polyethylene glycol stearate; block copolymers of ethylene oxide and propylene oxide; and salts of mono- and di-alkylphosphate esters; and also further substances described e.g. in McCutcheon's Detergents and Emulsifiers Annual, MC Publishing Corp., Ridgewood N.J. (1981).
  • Further adjuvants that can be used in pesticidal formulations include crystallisation inhibitors, viscosity modifiers, suspending agents, dyes, anti-oxidants, foaming agents, light absorbers, mixing auxiliaries, antifoams, complexing agents, neutralising or pH-modifying substances and buffers, corrosion inhibitors, fragrances, wetting agents, take-up enhancers, micronutrients, plasticisers, glidants, lubricants, dispersants, thickeners, antifreezes, microbicides, and liquid and solid fertilisers.
  • The compositions according to the invention can include an additive comprising an oil of vegetable or animal origin, a mineral oil, alkyl esters of such oils or mixtures of such oils and oil derivatives. The amount of oil additive in the composition according to the invention is generally from 0.01 to 10%, based on the mixture to be applied. For example, the oil additive can be added to a spray tank in the desired concentration after a spray mixture has been prepared. Preferred oil additives comprise mineral oils or an oil of vegetable origin, for example rapeseed oil, olive oil or sunflower oil, emulsified vegetable oil, alkyl esters of oils of vegetable origin, for example the methyl derivatives, or an oil of animal origin, such as fish oil or beef tallow. Preferred oil additives comprise alkyl esters of C8-C22 fatty acids, especially the methyl derivatives of C12-C18 fatty acids, for example the methyl esters of lauric acid, palmitic acid and oleic acid (methyl laurate, methyl palmitate and methyl oleate, respectively). Many oil derivatives are known from the Compendium of Herbicide Adjuvants, 10th Edition, Southern Illinois University, 2010.
  • The herbicidal compositions generally comprise from 0.1 to 99% by weight, especially from 0.1 to 95% by weight, compounds of formula (I) and from 1 to 99.9% by weight of a formulation adjuvant which preferably includes from 0 to 25% by weight of a surface-active substance. The inventive compositions generally comprise from 0.1 to 99% by weight, especially from 0.1 to 95% by weight, of compounds of the present invention and from 1 to 99.9% by weight of a formulation adjuvant which preferably includes from 0 to 25% by weight of a surface-active substance. Whereas commercial products may preferably be formulated as concentrates, the end user will normally employ dilute formulations. The rates of application vary within wide limits and depend on the nature of the soil, the method of application, the crop plant, the pest to be controlled, the prevailing climatic conditions, and other factors governed by the method of application, the time of application and the target crop. As a general guideline compounds may be applied at a rate of from 1 to 2000 I/ha, especially from 10 to 1000 I/ha.
  • Preferred formulations can have the following compositions (weight %):
  • Emulsifiable concentrates:
    active ingredient: 1 to 95%, preferably 60 to 90%
    surface-active agent: 1 to 30%, preferably 5 to 20%
    liquid carrier: 1 to 80%, preferably 1 to 35%
    • Dusts:
  • active ingredient: 0.1 to 10%, preferably 0.1 to 5%
    solid carrier: 99.9 to 90%, preferably 99.9 to 99%
    Suspension concentrates:
    active ingredient: 5 to 75%, preferably 10 to 50%
    water: 94 to 24%, preferably 88 to 30%
    surface-active agent: 1 to 40%, preferably 2 to 30%
    Wettable powders:
    active ingredient: 0.5 to 90%, preferably 1 to 80%
    surface-active agent: 0.5 to 20%, preferably 1 to 15%
    solid carrier: 5 to 95%, preferably 15 to 90%
    • Granules:
  • active ingredient: 0.1 to 30%, preferably 0.1 to 15%
    solid carrier: 99.5 to 70%, preferably 97 to 85%
  • The composition of the present may further comprise at least one additional pesticide. For example, the compounds according to the invention can also be used in combination with other herbicides or plant growth regulators. In a preferred embodiment the additional pesticide is a herbicide and/or herbicide safener.
  • Thus, compounds of formula (I) can be used in combination with one or more other herbicides to provide various herbicidal mixtures. Specific examples of such mixtures include (wherein “I” represents a compound of formula (I)):—I+acetochlor, I+acifluorfen (including acifluorfen-sodium), I+aclonifen, I+ametryn, I+amicarbazone, I+aminopyralid, I+aminotriazole, I+atrazine, I+beflubutamid-M, I+bensulfuron (including bensulfuron-methyl), I+bentazone, I+bicyclopyrone, I+bilanafos, I+bispyribac-sodium, I+bixlozone, I+bromacil, I+bromoxynil, I+butachlor, I+butafenacil, I+carfentrazone (including carfentrazone-ethyl), I+cloransulam (including cloransulam-methyl), 1+chlorimuron (including chlorimuron-ethyl), I+chlorotoluron, I+chlorsulfuron, I+cinmethylin, I+clacyfos, I+clethodim, I+clodinafop (including clodinafop-propargyl), I+clomazone, I+clopyralid, I+cyclopyranil, I+cyclopyrimorate, I+cyclosulfamuron, I+cyhalofop (including cyhalofop-butyl), I+2,4-D (including the choline salt and 2-ethylhexyl ester thereof), I+2,4-DB, I+desmedipham, I+dicamba (including the aluminium, aminopropyl, bis-aminopropylmethyl, choline, dichloroprop, diglycolamine, dimethylamine, dimethylammonium, potassium and sodium salts thereof) I+diclosulam, I+diflufenican, I+diflufenzopyr, I+dimethachlor, I+dimethenamid-P, I+diquat dibromide, diuron, I+ethalfluralin, I+ethofumesate, I+fenoxaprop (including fenoxaprop-P-ethyl), I+fenoxasulfone, I+fenquinotrione, I+fentrazamide, I+flazasulfuron, I+florasulam, I+florpyrauxifen (including florpyrauxifen-benzyl), I+fluazifop (including fluazifop-P-butyl), I+flucarbazone (including flucarbazone-sodium), I+flufenacet, I+flumetsulam, I+flumioxazin, I+fluometuron, I+flupyrsulfuron (including flupyrsulfuron-methyl-sodium), I+fluroxypyr (including fluroxypyr-meptyl), I+fomesafen, I+foramsulfuron, I+glufosinate (including the ammonium salt thereof), I+glyphosate (including the diammonium, isopropylammonium and potassium salts thereof), I+halauxifen (including halauxifen-methyl), I+haloxyfop (including haloxyfop-methyl), I+hexazinone, I+hydantocidin, I+imazamox, I+imazapic, I+imazapyr, I+imazethapyr, I+indaziflam, I+iodosulfuron (including iodosulfuron-methyl-sodium), I+iofensulfuron (including iofensulfuron-sodium), I+ioxynil, I+isoproturon, I+isoxaflutole, I+lancotrione, I+MCPA, I+MCPB, I+mecoprop-P, I+mesosulfuron (including mesosulfuron-methyl), I+mesotrione, I+metamitron, I+metazachlor, I+methiozolin, I+metolachlor, I+metosulam, I+metribuzin, I+metsulfuron, I+napropamide, I+nicosulfuron, I+norflurazon, I+oxadiazon, I+oxasulfuron, I+oxyfluorfen, I+paraquat dichloride, I+pendimethalin, I+penoxsulam, I+phenmedipham, I+picloram, I+pinoxaden, I+pretilachlor, I+primisulfuron-methyl, I+prometryne, I+propanil, I+propaquizafop, I+propyrisulfuron, I+propyzamide, I+prosulfocarb, I+prosulfuron, I+pyraclonil, I+pyraflufen (including pyraflufen-ethyl), I+pyrasulfotole, I+pyridate, I+pyriftalid, I+pyrimisulfan, I+pyroxasulfone, I+pyroxsulam, I+quinclorac, I+quinmerac, I+quizalofop (including quizalofop-P-ethyl and quizalofop-P-tefuryl), I+rimsulfuron, I+saflufenacil, I+sethoxydim, I+simazine, I+S-metalochlor, I+sulfentrazone, I+sulfosulfuron, I+tebuthiuron, I+tefuryltrione, I+tembotrione, I+terbuthylazine, I+terbutryn, I+tetflupyrolimet, I+thiencarbazone, I+thifensulfuron, I+tiafenacil, I+tolpyralate, I+topramezone, I+tralkoxydim, I+triafamone, I+triallate, I+triasulfuron, I+tribenuron (including tribenuron-methyl), I+triclopyr, I+trifloxysulfuron (including trifloxysulfuron-sodium), I+trifludimoxazin, I+trifluralin, I+triflusulfuron, I+ethyl 2-[[3-[2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)pyrimidin-1-yl]phenoxy]-2-pyridyl]oxy]acetate, I+3-(2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)phenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid ethyl ester, I+4-hydroxy-1-methoxy-5-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-one, I+4-hydroxy-1,5-dimethyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-one, I+5-ethoxy-4-hydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-one, I+4-hydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-one, I+4-hydroxy-1,5-dimethyl-3-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]imidazolidin-2-one, I+(4R)1-(5-tert-butylisoxazol-3-yl)-4-ethoxy-5-hydroxy-3-methyl-imidazolidin-2-one, I+3-[2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carbonyl]bicyclo[3.2.1]octane-2,4-dione, I+2-[2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carbonyl]-5-methyl-cyclohexane-1,3-dione, I+2-[2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carbonyl]cyclohexane-1,3-dione, I+2-[2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carbonyl]-5,5-dimethyl-cyclohexane-1,3-dione, I+6-[2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carbonyl]-2,2,4,4-tetramethyl-cyclohexane-1,3,5-trione, I+2-[2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carbonyl]-5-ethyl-cyclohexane-1,3-dione, I+2-[2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carbonyl]-4,4,6,6-tetramethyl-cyclohexane-1,3-dione, I+2-[6-cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxo-pyridazine-4-carbonyl]-5-methyl-cyclohexane-1,3-dione, I+3-[6-cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxo-pyridazine-4-carbonyl]bicyclo[3.2.1]octane-2,4-dione, I+2-[6-cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxo-pyridazine-4-carbonyl]-5,5-dimethyl-cyclohexane-1,3-dione, I+6-[6-cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxo-pyridazine-4-carbonyl]-2,2,4,4-tetramethyl-cyclohexane-1,3,5-trione, I+2-[6-cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxo-pyridazine-4-carbonyl]cyclohexane-1,3-dione, I+4-[2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carbonyl]-2,2,6,6-tetramethyl-tetrahydropyran-3,5-dione, I+4-[6-cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxo-pyridazine-4-carbonyl]-2,2,6,6-tetramethyl-tetrahydropyran-3,5-dione, I+4-amino-3-chloro-5-fluoro-6-(7-fluoro-1H-indol-6-yl)pyridine-2-carboxylic acid (including agrochemically acceptable esters thereof, for example, methyl 4-amino-3-chloro-5-fluoro-6-(7-fluoro-1H-indol-6-yl)pyridine-2-carboxylate).
  • The mixing partners of the compound of formula (I) may also be in the form of esters or salts, as mentioned e.g. in The Pesticide Manual, Fourteenth Edition, British Crop Protection Council, 2006.
  • The compound of formula (I) can also be used in mixtures with other agrochemicals such as fungicides, nematicides or insecticides, examples of which are given in The Pesticide Manual.
  • The mixing ratio of the compound of formula (I) to the mixing partner is preferably from 1:100 to 1000:1.
  • The mixtures can advantageously be used in the above-mentioned formulations (in which case “active ingredient” relates to the respective mixture of compound of formula (I) with the mixing partner).
  • Compounds of formula (I) of the present invention may also be combined with herbicide safeners. Preferred combinations (wherein “I” represents a compound of formula (I)) include:—I+benoxacor, I+cloquintocet (including cloquintocet-mexyl); I+cyprosulfamide; I+dichlormid; I+fenchlorazole (including fenchlorazole-ethyl); I+fenclorim; I+fluxofenim; 1+furilazole I+isoxadifen (including isoxadifen-ethyl); I+mefenpyr (including mefenpyr-diethyl); I+metcamifen and I+oxabetrinil.
  • Particularly preferred are mixtures of a compound of formula (I) with cyprosulfamide, isoxadifen (including isoxadifen-ethyl), cloquintocet (including cloquintocet-mexyl) and/or metcamifen.
  • The safeners of the compound of formula (I) may also be in the form of esters or salts, as mentioned e.g. in The Pesticide Manual, 14th Edition (BCPC), 2006. The reference to cloquintocet-mexyl also applies to a lithium, sodium, potassium, calcium, magnesium, aluminium, iron, ammonium, quaternary ammonium, sulfonium or phosphonium salt thereof as disclosed in WO 02/34048, and the reference to fenchlorazole-ethyl also applies to fenchlorazole, etc.
  • Preferably the mixing ratio of compound of formula (I) to safener is from 100:1 to 1:10, especially from 20:1 to 1:1.
  • The mixtures can advantageously be used in the above-mentioned formulations (in which case “active ingredient” relates to the respective mixture of compound of formula (I) with the safener).
  • The compounds of formula (I) of this invention are useful as herbicides. The present invention therefore further comprises a method for controlling unwanted plants comprising applying to the said plants or a locus comprising them, an effective amount of a compound of the invention or a herbicidal composition containing said compound. ‘Controlling’ means killing, reducing or retarding growth or preventing or reducing germination. Generally the plants to be controlled are unwanted plants (weeds). ‘Locus’ means the area in which the plants are growing or will grow.
  • The rates of application of compounds of formula (I) may vary within wide limits and depend on the nature of the soil, the method of application (pre-emergence; post-emergence; application to the seed furrow; no tillage application etc.), the crop plant, the weed(s) to be controlled, the prevailing climatic conditions, and other factors governed by the method of application, the time of application and the target crop. The compounds of formula (I) according to the invention are generally applied at a rate of from 10 to 2000 g/ha, especially from 50 to 1000 g/ha.
  • The application is generally made by spraying the composition, typically by tractor mounted sprayer for large areas, but other methods such as dusting (for powders), drip or drench can also be used.
  • Useful plants in which the composition according to the invention can be used include crops such as cereals, for example barley and wheat, cotton, oilseed rape, sunflower, maize, rice, soybeans, sugar beet, sugar cane and turf.
  • Crop plants can also include trees, such as fruit trees, palm trees, coconut trees or other nuts. Also included are vines such as grapes, fruit bushes, fruit plants and vegetables.
  • Crops are to be understood as also including those crops which have been rendered tolerant to herbicides or classes of herbicides (e.g. ALS-, GS-, EPSPS-, PPO-, ACCase- and HPPD-inhibitors) by conventional methods of breeding or by genetic engineering. An example of a crop that has been rendered tolerant to imidazolinones, e.g. imazamox, by conventional methods of breeding is Clearfield® summer rape (canola). Examples of crops that have been rendered tolerant to herbicides by genetic engineering methods include e.g. glyphosate- and glufosinate-resistant maize varieties commercially available under the trade names RoundupReady® and LibertyLink®.
  • Crops are also to be understood as being those which have been rendered resistant to harmful insects by genetic engineering methods, for example Bt maize (resistant to European corn borer), Bt cotton (resistant to cotton boll weevil) and also Bt potatoes (resistant to Colorado beetle). Examples of Bt maize are the Bt 176 maize hybrids of NK® (Syngenta Seeds). The Bt toxin is a protein that is formed naturally by Bacillus thuringiensis soil bacteria. Examples of toxins, or transgenic plants able to synthesise such toxins, are described in EP-A-451 878, EP-A-374 753, WO 93/07278, WO 95/34656, WO 03/052073 and EP-A-427 529. Examples of transgenic plants comprising one or more genes that code for an insecticidal resistance and express one or more toxins are KnockOut® (maize), Yield Gard® (maize), NuCOTIN33B® (cotton), Bollgard® (cotton), NewLeaf® (potatoes), NatureGard® and Protexcta®. Plant crops or seed material thereof can be both resistant to herbicides and, at the same time, resistant to insect feeding (“stacked” transgenic events). For example, seed can have the ability to express an insecticidal Cry3 protein while at the same time being tolerant to glyphosate.
  • Crops are also to be understood to include those which are obtained by conventional methods of breeding or genetic engineering and contain so-called output traits (e.g. improved storage stability, higher nutritional value and improved flavour).
  • Other useful plants include turf grass for example in golf-courses, lawns, parks and roadsides, or grown commercially for sod, and ornamental plants such as flowers or bushes.
  • Compounds of formula (I) and compositions of the invention can typically be used to control a wide variety of monocotyledonous and dicotyledonous weed species. Examples of monocotyledonous species that can typically be controlled include Alopecurus myosuroides, Avena fatua, Brachiaria plantaginea, Bromus tectorum, Cyperus esculentus, Digitaria sanguinalis, Echinochloa crus-galli, Lolium perenne, Lolium multiflorum, Panicum miliaceum, Poa annua, Setaria viridis, Setaria faberi and Sorghum bicolor. Examples of dicotyledonous species that can be controlled include Abutilon theophrasti, Amaranthus retroflexus, Bidens pilosa, Chenopodium album, Euphorbia heterophylla, Galium aparine, Ipomoea hederacea, Kochia scoparia, Polygonum convolvulus, Sida spinosa, Sinapis arvensis, Solanum nigrum, Stellaria media, Veronica persica and Xanthium strumarium.
  • The compounds of formula (I) are also useful for pre-harvest desiccation in crops, for example, but not limited to, potatoes, soybean, sunflowers and cotton. Pre-harvest desiccation is used to desiccate crop foliage without significant damage to the crop itself to aid harvesting.
  • Compounds/compositions of the invention are particularly useful in non-selective burn-down applications, and as such may also be used to control volunteer or escape crop plants.
  • Various aspects and embodiments of the present invention will now be illustrated in more detail by way of example. It will be appreciated that modification of detail may be made without departing from the scope of the invention.
    • EXAMPLES
  • The Examples which follow serve to illustrate, but do not limit, the invention.
    • Formulation Examples
  • Wettable powders
    a) b) c)
    active ingredients 25% 50% 75%
    sodium lignosulfonate  5%  5% —
    sodium lauryl sulfate  3% —  5%
    sodium diisobutylnaphthalenesulfonate —  6% 10%
    phenol polyethylene glycol ether —  2% —
    (7-8 mol of ethylene oxide)
    highly dispersed silicic acid  5% 10% 10%
    Kaolin 62% 27% —
  • The combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording wettable powders that can be diluted with water to give suspensions of the desired concentration.
    • Emulsifiable Concentrate
  • active ingredients 10%
    octylphenol polyethylene glycol ether  3%
    (4-5 mol of ethylene oxide)
    calcium dodecylbenzenesulfonate  3%
    castor oil polyglycol ether (35 mol of  4%
    ethylene oxide)
    Cyclohexanone 30%
    xylene mixture 50%
  • Emulsions of any required dilution, which can be used in plant protection, can be obtained from this concentrate by dilution with water.
  • Dusts
    a) b) c)
    Active ingredients  5%  6%  4%
    Talcum 95% — —
    Kaolin — 94% —
    mineral filler — — 96%
      • Ready-for-use dusts are obtained by mixing the combination with the carrier and grinding the mixture in a suitable mill.
  • Extruder Granules
  •
    Active ingredients 15%
    sodium lignosulfonate  2%
    carboxymethylcellulose  1%
    Kaolin 82%
  • The combination is mixed and ground with the adjuvants, and the mixture is moistened with water. The mixture is extruded and then dried in a stream of air.
    • Coated Granules
  • Active ingredients 8%
    polyethylene glycol (mol. wt. 200) 3%
    Kaolin 89% 
  • The finely ground combination is uniformly applied, in a mixer, to the kaolin moistened with polyethylene glycol. Non-dusty coated granules are obtained in this manner.
    • Suspension Concentrate
  • active ingredients 40%
    propylene glycol 10%
    nonylphenol polyethylene glycol ether (15 mol of ethylene oxide)  6%
    Sodium lignosulfonate 10%
    carboxymethylcellulose  1%
    silicone oil (in the form of a 75% emulsion in water)  1%
    Water 32%
  • The finely ground combination is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water.
    • Slow Release Capsule Suspension
  • 28 parts of the combination are mixed with 2 parts of an aromatic solvent and 7 parts of toluene diisocyanate/polymethylene-polyphenylisocyanate-mixture (8:1). This mixture is emulsified in a mixture of 1.2 parts of polyvinylalcohol, 0.05 parts of a defoamer and 51.6 parts of water until the desired particle size is achieved. To this emulsion a mixture of 2.8 parts 1,6-diaminohexane in 5.3 parts of water is added. The mixture is agitated until the polymerization reaction is completed.
  • The obtained capsule suspension is stabilized by adding 0.25 parts of a thickener and 3 parts of a dispersing agent. The capsule suspension formulation contains 28% of the active ingredients. The medium capsule diameter is 8-15 microns.
  • The resulting formulation is applied to seeds as an aqueous suspension in an apparatus suitable for that purpose.
    • List of Abbreviations
  • Boc=tert-butyloxycarbonyl
    br=broad
    CDCl3=chloroform-d
    CD3OD=methanol-d
    ° C.=degrees Celsius
    D2O=water-d
    DCM=dichloromethane
    d=doublet
    dd=double doublet
    dt=double triplet
    DMSO=dimethylsulfoxide
    EtOAc=ethyl acetate
    h=hour(s)
    HCl=hydrochloric acid
    HPLC=high-performance liquid chromatography (description of the apparatus and the methods used for HPLC are given below)
    m=multiplet
    M=molar
    min=minutes
    MHz=mega hertz
    mL=millilitre
    mp=melting point
    ppm=parts per million
    q=quartet
    quin=quintet
    rt=room temperature
    s=singlet
    t=triplet
    THE=tetrahydrofuran
    • LC/MS=Liquid Chromatography Mass Spectrometry Preparative Reverse Phase HPLC Method:
  • Compounds purified by mass directed preparative HPLC using ES+/ES− on a Waters FractionLynx Autopurification system comprising a 2767 injector/collector with a 2545 gradient pump, two 515 isocratic pumps, SFO, 2998 photodiode array (Wavelength range (nm): 210 to 400), 2424 ELSD and QDa mass spectrometer. A Waters Atlantis T3 5 micron 19×10 mm guard column was used with a Waters Atlantis T3 OBD, 5 micron 30×100 mm prep column.
  • Ionisation method: Electrospray positive and negative: Cone (V) 20.00, Source Temperature (° C.) 120, Cone Gas Flow (L/Hr.) 50
  • Mass range (Da): positive 100 to 800, negative 115 to 800.
  • The preparative HPLC was conducted using an 11.4 minute run time (not using at column dilution, bypassed with the column selector), according to the following gradient table:
  • Time (mins) Solvent A (%) Solvent B (%) Flow (ml/min)
    0.00 100 0 35
    2.00 100 0 35
    2.01 100 0 35
    7.0 90 10 35
    7.3 0 100 35
    9.2 0 100 35
    9.8 99 1 35
    11.35 99 1 35
    11.40 99 1 35
    515 pump 0 ml/min Acetonitrile (ACD)
    515 pump 1 ml/min 90% Methanol/10% Water (make up pump)
    Solvent A: Water with 0.05% Trifluoroacetic Acid
    Solvent B: Acetonitrile with 0.05% Trifluoroacetic Acid
    • Preparation Examples Example 1: Preparation of 2-[4-[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]pyridin-1-ium-1-yl]acetic acid 2,2,2-trifluoroacetate A1
  • Figure US20220104493A1-20220407-C00071
    • Step 1: Preparation of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridin-1-ium chloride
  • Figure US20220104493A1-20220407-C00072
  • A mixture of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2 g) and aqueous hydrochloric acid (4M in 1,4-dioxane, 19 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was triturated with ether to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridin-1-ium chloride as a white solid.
  • 1H NMR (400 MHz, D2O) 6.28-6.21 (m, 1H), 3.69-3.62 (m, 2H), 3.21 (t, 2H), 2.41-2.24 (m, 2H), 1.12 (s, 12H) (NH proton missing)
    • Step 2: Preparation of tert-butyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]acetate
  • Figure US20220104493A1-20220407-C00073
  • A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridin-1-ium chloride (1.89 g), acetonitrile (31.6 mL), potassium carbonate (2.62 g) and tert-butyl 2-chloroacetate (1.35 mL) was heated at 90° C. for 20 hours. The reaction mixture was cooled and partitioned between water and dichloromethane, then further extracted with dichloromethane (×2). The combined organic phase was dried over magnesium sulfate and concentrated to give tert-butyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]acetate as a yellow gum.
  • 1H NMR (400 MHz, CDCl3) 6.52-6.43 (m, 1H), 3.24-3.15 (m, 4H), 2.68 (t, 2H), 2.34-2.26 (m, 2H), 1.46 (s, 9H), 1.25 (s, 12H)
    • Step 3: Preparation of tert-butyl 2-[4-[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]-3,6-dihydro-2H-pyridin-1-yl]acetate
  • Figure US20220104493A1-20220407-C00074
  • A mixture of tert-butyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]acetate (0.838 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.155 g), 5-chloro-3-(trifluoromethyl)-1,2,4-thiadiazole (0.4 g), sodium carbonate (0.899 g), 1,4-dioxane (7.43 mL) and water (7.43 mL) was degassed with nitrogen then heated at 120° C. under microwave irradiation for 1 hour. The reaction mixture was cooled to room temperature then filtered through diatomaceous earth and partitioned between water and ethyl acetate. The organic phase was concentrated then purified by silica gel chromatography eluting with 0 to 50% ethyl acetate in cyclohexane to give tert-butyl 2-[4-[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]-3,6-dihydro-2H-pyridin-1-yl]acetate.
  • 1H NMR (400 MHz, CDCl3) 6.83-6.99 (m, 1H), 3.44-3.50 (m, 2H), 3.30-3.33 (m, 2H), 2.90-2.96 (m, 2H), 2.69-2.75 (m, 2H), 1.48-1.51 (m, 9H)
    • Step 4: Preparation of 2-[4-[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]pyridin-1-ium-1-yl]acetic acid 2,2,2-trifluoroacetate A1
  • To a solution of tert-butyl 2-[4-[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]-3,6-dihydro-2H-pyridin-1-yl]acetate (0.43 g) in 1,4-dioxane (6.6 mL) was added N-bromosuccinimide (0.294 g) in one portion followed by stirring at room temperature for 2 hours. To the reaction mixture was then added aqueous hydrochloric acid (2.4 mL, 4M in 1,4-dioxane) with additional stirring for 5 hours at room temperature. The reaction mixture was diluted with tert-butyl methyl ether (20 mL) and the resulting solid was filtered, washed with additional tert-butyl methyl ether then purified by preparative reverse phase HPLC (trifluoroacetic acid was present in the eluent) to afford 2-[4-[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]pyridin-1-ium-1-yl]acetic acid 2,2,2-trifluoroacetate.
  • 1H NMR (400 MHz, D2O) 9.06 (d, 2H), 8.69 (d, 2H), 5.41 (s, 2H) (CO2H proton missing)
    • Example 2: Preparation of [4-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]methanesulfonate A2
  • Figure US20220104493A1-20220407-C00075
    • Step 1: Preparation of (NE)-N-[1-(dimethylamino)ethylidene]pyridine-4-carbothioamide
  • Figure US20220104493A1-20220407-C00076
  • A mixture of pyridine-4-carbothioamide (1 g) and 1,1-dimethoxy-N,N-dimethyl-ethanamine (1.05 mL) were stirred together at room temperature for one hour. The reaction was concentrated to give (NE)-N-[1-(dimethylamino)ethylidene]pyridine-4-carbothioamide as a red gum which crystallised on standing.
  • 1H NMR (400 MHz, CD3OD) 8.55-8.51 (m, 2H), 8.11-8.08 (m, 2H), 3.37 (s, 3H), 3.26-3.21 (m, 3H), 2.52 (s, 3H)
    • Step 2: Preparation of 3-methyl-5-(4-pyridyl)-1,2,4-thiadiazole
  • Figure US20220104493A1-20220407-C00077
  • To a solution of (NE)-N-[1-(dimethylamino)ethylidene]pyridine-4-carbothioamide (1.5 g) and pyridine (1.23 mL) in ethanol (36 mL) at room temperature was added a second solution of hydroxylamine-O-sulfonic acid (0.9 g) in methanol (14 mL). The reaction mixture was stirred at room temperature for one hour then quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic phase was concentrated, triturated with hexane then dried to give 3-methyl-5-(4-pyridyl)-1,2,4-thiadiazole as a brown solid.
  • 1H NMR (400 MHz, CD3OD) 8.78-8.71 (m, 2H), 8.00-7.96 (m, 2H), 2.72 (s, 3H)
    • Step 3: Preparation of methyl 2-[4-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]acetate bromide
  • Figure US20220104493A1-20220407-C00078
  • A mixture of 3-methyl-5-(4-pyridyl)-1,2,4-thiadiazole (1.165 g), acetonitrile (20 mL) and methyl 2-bromoacetate (0.93 mL) was heated at 80° C. for 25 hours. The reaction mixture was partitioned between water and dichloromethane and the aqueous phase was concentrated to give methyl 2-[4-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]acetate bromide which was used without further purification.
    • Step 4: Preparation of 2-[4-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]acetic acid chloride A59
  • Figure US20220104493A1-20220407-C00079
  • A solution of crude methyl 2-[4-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]acetate bromide (1.7 g) and 2M aqueous hydrochloric acid (45 mL) was heated at 50° C. for 4 hours. The reaction mixture was then concentrated to give 2-[4-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]acetic acid chloride.
  • 1H NMR (400 MHz, D2O) 8.93-8.89 (m, 2H), 8.51-8.46 (m, 2H), 5.37 (s, 2H), 2.67 (s, 3H) (CO2H proton missing)
    • Step 5: Preparation of [4-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]methanesulfonate A2
  • A mixture of 2-[4-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]acetic acid chloride (0.83 g) and trimethylsilyl chlorosulfonate (11 mL) was heated at 120° C. overnight. The reaction mixture was cooled to room temperature and partitioned between water and dichloromethane. The aqueous phase was then concentrated and purified by preparative reverse phase HPLC to afford [4-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]methanesulfonate as a white solid.
  • 1H NMR (400 MHz, D2O) 9.02-9.20 (m, 2H) 8.55-8.68 (m, 2H) 5.58-5.81 (m, 2H) 2.65-2.82 (m, 3H)
    • Example 3: Preparation of [4-(thiadiazol-5-yl)pyridin-1-ium-1-yl]methanesulfonate A3
  • Figure US20220104493A1-20220407-C00080
    • Step 1: Preparation of methyl 2-diazo-3-oxo-3-(4-pyridyl)propanoate
  • Figure US20220104493A1-20220407-C00081
  • To a mixture of methyl 3-oxo-3-(4-pyridyl)propanoate (4 g) and 4-acetamidobenzenesulfonyl azide (6.082 g) in dichloromethane (130 mL) was added triethylamine (9.43 mL) drop wise at 0° C. The reaction mixture was slowly warmed to room temperature then stirred overnight. After filtration through silica, followed by and washing with dichloromethane, the filtrate was then concentrated to afford methyl 2-diazo-3-oxo-3-(4-pyridyl)propanoate as a yellow gum.
  • 1H NMR (400 MHz, CDCl3) 8.78-8.71 (m, 2H), 7.45-7.40 (m, 2H) 3.79 (s, 3H)
    • Step 2: Preparation of methyl 5-(4-pyridyl)thiadiazole-4-carboxylate
  • Figure US20220104493A1-20220407-C00082
  • A mixture of methyl 2-diazo-3-oxo-3-(4-pyridyl)propanoate (4.58 g) and Lawesson's reagent (11.2 g) in toluene (112 mL) was heated at 120° C. overnight. The reaction mixture was concentrated then purified by silica gel chromatography eluting with 0 to 50% methanol in dichloromethane to give methyl 5-(4-pyridyl)thiadiazole-4-carboxylate which was used in the next step without further purification.
    • Step 3: Preparation of 5-(4-pyridyl)thiadiazole-4-carboxylic acid
  • Figure US20220104493A1-20220407-C00083
  • A mixture of crude methyl 5-(4-pyridyl)thiadiazole-4-carboxylate (4 g) and 2M aqueous hydrochloric acid (150 mL) was heated at reflux for 3 hours. The reaction mixture was concentrated and partitioned between water and ethyl acetate. The aqueous layer was concentrated to give 5-(4-pyridyl)thiadiazole-4-carboxylic acid which was used in the next step without further purification.
    • Step 4: Preparation of 5-pyridin-1-ium-4-ylthiadiazole 2,2,2-trifluoroacetate
  • Figure US20220104493A1-20220407-C00084
  • A mixture of 5-(4-pyridyl)thiadiazole-4-carboxylic acid (3.35 g), water (5 mL) and 1,4-dioxane (80 mL) was heated at 100° C. overnight. The reaction mixture was concentrated and purified by preparative reverse phase HPLC (trifluoroacetic acid was present in the eluent) to afford 5-pyridin-1-ium-4-ylthiadiazole 2,2,2-trifluoroacetate as a white solid.
  • 1H NMR (400 MHz, CD3OD) 9.45 (s, 1H), 8.90-8.83 (m, 2H), 8.21-8.16 (m, 2H)
    • Step 5: Preparation of methyl 2-[4-(thiadiazol-5-yl)pyridin-1-ium-1-yl]acetate bromide A8
  • Figure US20220104493A1-20220407-C00085
  • A mixture of 5-pyridin-1-ium-4-ylthiadiazole 2,2,2-trifluoroacetate (0.5 g), acetonitrile (10 mL) and methyl 2-bromoacetate (0.44 mL) was heated at 80° C. for 25 hours. The reaction mixture was concentrated and partitioned between water and dichloromethane. The aqueous layer was concentrated to give methyl 2-[4-(thiadiazol-5-yl)pyridin-1-ium-1-yl]acetate bromide as a brown gum.
  • 1H NMR (400 MHz, D2O) 9.39-9.45 (m, 1H) 8.85-8.93 (m, 2H) 8.35-8.44 (m, 2H) 5.55 (s, 2H) 3.73-3.84 (m, 3H)
    • Step 6: Preparation of 2-[4-(thiadiazol-5-yl)pyridin-1-ium-1-yl]acetic acid chloride A9
  • Figure US20220104493A1-20220407-C00086
  • A mixture of methyl 2-[4-(thiadiazol-5-yl)pyridin-1-ium-1-yl]acetate bromide (0.46 g) and 2M aqueous hydrochloric acid (20 mL) was heated at 50° C. for 5 hours. The reaction mixture was concentrated to give 2-[4-(thiadiazol-5-yl)pyridin-1-ium-1-yl]acetic acid chloride.
  • 1H NMR (400 MHz, D2O) 9.38-9.43 (m, 1H) 8.83-8.90 (m, 2H) 8.33-8.40 (m, 2H) 5.40 (s, 2H) (CO2H proton missing)
    • Step 7: Preparation of [4-(thiadiazol-5-yl)pyridin-1-ium-1-yl]methanesulfonate A3
  • A mixture of 2-[4-(thiadiazol-5-yl)pyridin-1-ium-1-yl]acetic acid chloride (0.46 g) and trimethylsilyl chlorosulfonate (5.4 mL) was heated at 120° C. overnight. The reaction mixture was cooled to room temperature and partitioned between water and dichloromethane. The aqueous phase was concentrated then purified by preparative reverse phase HPLC to afford [4-(thiadiazol-5-yl)pyridin-1-ium-1-yl]methanesulfonate as a white solid.
  • 1H NMR (400 MHz, D2O) 9.41-9.49 (m, 1H) 8.95-9.04 (m, 2H) 8.37-8.49 (m, 2H) 5.68 (br s, 2H)
    • Example 4: Preparation of 2-[4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]ethanesulfonate A5
  • Figure US20220104493A1-20220407-C00087
  • A mixture of 5-(4-pyridyl)-1,2,4-thiadiazole (300 mg), sodium 2-bromoethanesulfonic acid (465 mg) and water (6 mL) was heated at 100° C. overnight. The reaction mixture was concentrated and purified by preparative reverse phase HPLC to afford 2-[4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]ethanesulfonate
  • 1H NMR (400 MHz, D2O) 9.02-9.11 (m, 2H) 8.87-8.99 (m, 1H) 8.47-8.60 (m, 2H) 4.94-5.05 (m, 2H) 3.48-3.61 (m, 2H)
    • Example 5: Preparation of 3-[4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]propanoic acid chloride A7
  • Figure US20220104493A1-20220407-C00088
    • Step 1: Preparation of methyl 3-[4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]propanoate 2,2,2-trifluoroacetate
  • Figure US20220104493A1-20220407-C00089
  • A mixture of 5-(4-pyridyl)-1,2,4-thiadiazole (0.3 g), acetonitrile (6 mL) and methyl 3-bromopropionate (0.31 mL) was heated at 80° C. for 25 hours. The reaction mixture was cooled and partitioned between water and dichloromethane. The aqueous layer was concentrated then purified by preparative reverse phase HPLC to afford methyl 3-[4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]propanoate 2,2,2-trifluoroacetate as a white solid
  • 1H NMR (400 MHz, D2O) 9.07 (d, 2H), 8.94 (s, 1H), 8.54 (d, 2H), 4.90 (t, 2H), 3.60 (s, 3H), 3.18 (t, 2H)
    • Step 2: Preparation of 3-[4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]propanoic acid chloride A7
  • A mixture of methyl 3-[4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]propanoate (50 mg) and 2M aqueous hydrochloric acid (1 mL) was heated at 50° C. for 5 hours. The reaction mixture was concentrated to give 3-[4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]propanoic acid chloride as a white solid.
  • 1H NMR (400 MHz, D2O) 9.05 (d, 2H), 8.92 (s, 1H), 8.51 (d, 2H), 4.87 (t, 2H), 3.15 (t, 2H) (CO2H proton missing)
    • Example 6: Preparation of [4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]methanesulfonate A4
  • Figure US20220104493A1-20220407-C00090
    • Step 1: Preparation of tert-butyl 4-(1,2,4-thiadiazol-5-yl)-3,6-dihydro-2H-pyridine-1-carboxylate
  • Figure US20220104493A1-20220407-C00091
  • To a mixture of 5-bromo-1,2,4-thiadiazole (5 g), 1,4-dioxane (50 mL) and water (17 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (10 g), cesium carbonate (15 g) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (2.5 g). The mixture was purged with nitrogen then heated at 95° C. for 19 hours. The mixture was filtered through celite and the filtrate was concentrated and purified by silica gel chromatography eluting with 0 to 30% ethyl acetate in cyclohexane to give tert-butyl 4-(1,2,4-thiadiazol-5-yl)-3,6-dihydro-2H-pyridine-1-carboxylate as a yellow liquid.
  • 1H NMR (400 MHz, CDCl3) 8.61 (s, 1H), 6.81 (br s, 1H), 4.18 (br d, 2H), 3.68 (br t, 2H), 2.68 (br dd, 2H), 1.49 (s, 9H)
    • Step 2: Preparation of 5-(1,2,3,6-tetrahydropyridin-4-yl)-1,2,4-thiadiazole hydrochloride
  • Figure US20220104493A1-20220407-C00092
  • A mixture of tert-butyl 4-(1,2,4-thiadiazol-5-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (5 g) and hydrochloric acid (4M in dioxane, 26 mL) was stirred at room temperature for 1.5 hours. The mixture was concentrated, azeotroped with toluene and the resulting residue was washed with ethyl acetate (2×40 mL) and dried to give 5-(1,2,3,6-tetrahydropyridin-4-yl)-1,2,4-thiadiazole hydrochloride as a pale pink solid.
  • 1H NMR (400 MHz, D2O) 8.63 (s, 1H), 6.80 (tt, 1H), 3.90 (q, 2H), 3.46 (t, 2H), 2.85 (qt, 2H)
    • Step 3: Preparation of sodium [4-(1,2,4-thiadiazol-5-yl)-3,6-dihydro-2H-pyridin-1-yl]methanesulfonate
  • Figure US20220104493A1-20220407-C00093
  • To a solution of 5-(1,2,3,6-tetrahydropyridin-4-yl)-1,2,4-thiadiazole hydrochloride (2.5 g) in water (12 mL) was added sodium hydroxide (0.54 g). Sodium hydroxymethanesulfonate (formaldehyde sodium bisulfite adduct, 1.6 g) was added and the mixture was stirred at room temperature for 1 hour, periodically checking the pH of the solution was maintained between pH 10 and 11 by the addition of further aqueous 2M sodium hydroxide. The mixture was freeze dried to give sodium [4-(1,2,4-thiadiazol-5-yl)-3,6-dihydro-2H-pyridin-1-yl]methanesulfonate as an off-white solid, which was used without further purification.
  • 1H NMR (400 MHz, D2O) 8.61 (s, 1H), 6.86 (td, 1H), 3.90 (s, 2H), 3.66 (q, 2H), 3.15 (t, 2H), 2.67-2.62 (m, 2H)
    • Step 4: Preparation of [4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]methanesulfonate A4
  • To a mixture of sodium [4-(1,2,4-thiadiazol-5-yl)-3,6-dihydro-2H-pyridin-1-yl]methanesulfonate (2.452 g) in dry acetonitrile (15.8 mL), under nitrogen atmosphere, was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3.67 g) portion wise over 3 minutes. The mixture was stirred at 25° C. for 18 hours. To the mixture was added trimethylsilyl bromide (0.718 mL). After 15 minutes stirring tetrahydrofuran (47.4 mL) was added and the mixture stirred for a further 20 minutes. The solid was filtered off, washed with tetrahydrofuran and dried. The solid was purified by preparative reverse phase HPLC to give [4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]methanesulfonate as an off-white solid.
  • 1H NMR (400 MHz, D2O) 9.25-9.02 (m, 3H), 8.81-8.66 (m, 2H), 5.85-5.74 (m, 2H)
    • Example 7: Preparation of 2-[4-(thiadiazol-4-yl)pyridin-1-ium-1-yl]ethyl sulfate A65
  • Figure US20220104493A1-20220407-C00094
  • A mixture of 4-(4-pyridyl)thiadiazole (0.1 g), 1,3,2-dioxathiolane 2,2-dioxide (0.087 g) and 1,2-dichloroethane (6 mL) was heated at 85° C. for 18 hours. The resulting precipitate was filtered off and air dried to give 2-[4-(thiadiazol-4-yl)pyridin-1-ium-1-yl]ethyl sulfate as a white solid.
  • 1H NMR (400 MHz, DMSO-d6) 10.23-10.36 (m, 1H), 9.09-9.24 (m, 2H), 8.73-8.96 (m, 2H), 4.73-4.94 (m, 2H), 4.18-4.34 (m, 2H)
    • Example 8: Preparation of N-methyl-5-(4-pyridyl)isoxazole-3-carboxamide
  • Figure US20220104493A1-20220407-C00095
  • To a solution of 5-(4-pyridyl)isoxazole-3-carboxylic acid (0.5 g) in dichloromethane (14 mL) was added 1-chloro-N,N,2-trimethyl-prop-1-en-1-amine (0.35 mL) drop wise. After stirring for 30 minutes a solution of methanamine (2M in tetrahydrofuran, 2.63 mL) and N,N′-diisopropylethylamine (0.504 mL) in dichloromethane was added drop wise. The resulting mixture was stirred overnight at room temperature. The mixture was partitioned between dichloromethane and water. The organic layer was concentrated to give N-methyl-5-(4-pyridyl)isoxazole-3-carboxamide as a yellow solid.
  • 1H NMR (400 MHz, DMSO-d6) 8.90-8.81 (m, 1H), 8.81-8.75 (m, 2H), 7.95-7.87 (m, 2H), 7.67 (s, 1H), 2.81 (d, 3H)
    • Example 9: Preparation of 5-(4-pyridyl)-1,2,4-oxadiazole
  • Figure US20220104493A1-20220407-C00096
    • Step 1: Preparation of N-(dimethylaminomethylene)pyridine-4-carboxamide
  • Figure US20220104493A1-20220407-C00097
  • A mixture of pyridine-4-carboxamide (5 g) and 1,1-dimethoxy-N,N-dimethyl-methanamine (5.46 mL) were stirred together at room temperature for 4 hours. The mixture was concentrated and purified by silica gel chromatography eluting with 0 to 50% methanol in acetonitrile to give N-(dimethylaminomethylene)pyridine-4-carboxamide as a white solid.
  • 1H NMR (400 MHz, CDCl3) 8.77-8.70 (m, 2H), 8.69-8.65 (m, 1H), 8.08-8.02 (m, 2H), 3.24 (d, 6H)
    • Step 2: Preparation of 5-(4-pyridyl)-1,2,4-oxadiazole
  • To N-(dimethylaminomethylene)pyridine-4-carboxamide (3.99 g) was added a solution of dioxane (27 mL), hydroxylamine (50% aqueous solution, 2.07 mL) and acetic acid (32 mL). The mixture was heated at 90° C. for 1 hour. The reaction mixture was concentrated and partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane. The organic layer was concentrated and purified by preparative reverse phase HPLC to give 5-(4-pyridyl)-1,2,4-oxadiazole as a white solid.
  • 1H NMR (400 MHz, CD3OD) 8.95-8.88 (m, 3H), 8.30-8.25 (m, 2H)
    • Example 10: Preparation of 4-(2-methyltetrazol-5-yl)pyridine
  • Figure US20220104493A1-20220407-C00098
  • To a mixture of 4-(1H-tetrazol-5-yl)pyridine (0.4 g) and N,N-dimethylformamide (3.5 mL) was added dimethyl carbonate (2.2 mL) and 1,4-diazabicyclo[2.2.2]octane (0.032 g) and the mixture was heated at 130° C. overnight. The reaction mixture was cooled to room temperature and 0.25M aqueous sodium hydroxide (11 mL) was added and the mixture extracted with ethyl acetate (×3). The combined organic layers were washed with water and concentrated to give 4-(2-methyltetrazol-5-yl)pyridine.
  • 1H NMR (400 MHz, CDCl3) 8.80-8.75 (m, 2H), 8.04-7.99 (m, 2H), 4.45 (s, 3H)
  • The material is isolated as a mixture with 4-(I-methyltetrazol-5-yl)pyridine.
  • Figure US20220104493A1-20220407-C00099
  • 1H NMR (400 MHz, CDCl3) 8.91-8.85 (m, 2H), 7.72-7.68 (m, 2H), 4.26 (s, 3H) Separation of the isomers occurred after alkylation of the pyridine.
    • Example 11: Preparation of methoxy-[[4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]methyl]phosphinate A30
  • Figure US20220104493A1-20220407-C00100
    • Step 1: Preparation of dimethoxyphosphorylmethanol
  • Figure US20220104493A1-20220407-C00101
  • To a solution of methoxyphosphonoyloxymethane (8 g) in methanol (40 mL) was added paraformaldehyde (2.18 g) and potassium carbonate (0.502 g) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through celite and washed with dichloromethane (50 mL). The filtrate was concentrated then purified by silica gel chromatography eluting with a mixture of ethyl acetate in n-hexanes to give dimethoxyphosphorylmethanol as colourless liquid.
  • 1H NMR (400 MHz, CDCl3) 3.96-3.94 (d, 2H), 3.83-3.80 (d, 6H) (OH proton missing)
    • Step 2: Preparation of dimethoxyphosphorylmethyl trifluoromethanesulfonate
  • Figure US20220104493A1-20220407-C00102
  • To a solution of dimethoxyphosphorylmethanol (5 g) in dichloromethane (50 mL) at −78° C., under nitrogen atmosphere, was added 2,6-lutidine (6.94 mL) and triflic anhydride (6.0 mL). The resulting reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 hour.
  • The reaction mixture was poured into water and extracted with dichloromethane (2×50 mL). The combined organic layers were washed with 1M aqueous hydrochloric acid (50 mL), dried over sodium sulfate and concentrated to afford dimethoxyphosphorylmethyl trifluoromethanesulfonate as pale yellow liquid.
  • 1H NMR (400 MHz, CDCl3) 4.67-4.64 (d, 2H), 3.90-3.87 (d, 6H)
    • Step 3: Preparation of 5-[1-(dimethoxyphosphorylmethyl)pyridin-1-ium-4-yl]-1,2,4-thiadiazole trifluoromethanesulfonate A77
  • Figure US20220104493A1-20220407-C00103
  • To a solution of 5-(4-pyridyl)-1,2,4-thiadiazole (1.5 g) in tetrahydrofuran (20 mL) was added dimethoxyphosphorylmethyl trifluoromethanesulfonate (3.56 g) at room temperature. The resulting mixture was heated at 60° C. for 16 hours. The reaction mixture was concentrated and the residue was dissolved in water (25 mL) and washed with dichloromethane (2×25 mL). The water layer was concentrated and purified by reverse phase HPLC (100% water) to afford 5-[1-(dimethoxyphosphorylmethyl)pyridin-1-ium-4-yl]-1,2,4-thiadiazole trifluoromethanesulfonate as a light brown solid.
  • 1H NMR (400 MHz, DMSO-d6) 9.33 (s, 1H), 9.22-9.17 (m, 2H), 8.88-8.83 (m, 2H), 5.54 (d, 2H), 3.83-3.76 (m, 6H)
    • Step 4: Preparation of methoxy-[[4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]methyl]phosphinate A30
  • To a mixture of 5-[1-(dimethoxyphosphorylmethyl)pyridin-1-ium-4-yl]-1,2,4-thiadiazole trifluoromethanesulfonate (0.3 g) in dichloromethane (10 mL) was added bromotrimethylsilane (0.1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was dissolved in water (25 mL) and washed with dichloromethane (2×25 mL). The water layer was concentrated and purified by reverse phase HPLC (100% water) to give methoxy-[[4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]methyl]phosphinate as an off-white solid.
  • 1H NMR (400 MHz, D2O) 8.96-8.88 (m, 3H), 8.54 (d, 2H), 4.90-4.83 (m, 2H), 3.54 (d, 3H)
    • Example 12: Preparation of hydroxy-[[4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]methyl]phosphinate A32
  • Figure US20220104493A1-20220407-C00104
  • To a solution of 5-[1-(dimethoxyphosphorylmethyl)pyridin-1-ium-4-yl]-1,2,4-thiadiazole trifluoromethanesulfonate (0.3 g) in dichloromethane (10 ml) was added bromotrimethylsilane (0.5 mlx) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and the residue was dissolved in water (25 ml) and washed with dichloromethane (2×25 mL). The water layer was concentrated and purified by reverse phase HPLC (100% water) to give hydroxy-[[4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]methyl]phosphinate as a colourless gum.
  • 1H NMR (400 MHz, D2O) 9.01-8.86 (m, 3H), 8.54 (d, 2H), 4.84-4.78 (m, 2H) (POH proton missing)
    • Example 13: Preparation of methyl-[[4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]methyl]phosphinate A10
  • Figure US20220104493A1-20220407-C00105
    • Step 1: Preparation of [ethoxy(methyl)phosphoryl]methanol
  • Figure US20220104493A1-20220407-C00106
  • To a solution of 1-[ethoxy(methyl)phosphoryl]oxyethane (3 g) in acetonitrile (30 mL) was added triethylamine (0.668 g), paraformaldehyde (0.727 g) and water (0.436 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by silica gel chromatography eluting with a mixture of methanol in dichloromethane to give [ethoxy(methyl)phosphoryl]methanol as a colourless liquid.
  • 1H NMR (400 MHz, CDCl3) 5.31-5.17 (m, 1H), 4.12-4.08 (m, 2H), 3.87-3.82 (m, 2H), 1.55-1.51 (d, 3H), 1.35-1.31 (t, 3H)
    • Step 2: Preparation of [ethoxy(methyl)phosphoryl]methyl trifluoromethanesulfonate
  • Figure US20220104493A1-20220407-C00107
  • To a solution of [ethoxy(methyl)phosphoryl]methanol (2 g) in dichloromethane (30 mL) at −78° C., under nitrogen atmosphere, was added 2,6-lutidine (2.68 g) and triflic anhydride (2.8 mL). The resulting reaction mixture was allowed to warm to room temperature and stirred at room temperature for 3 hours. The reaction mixture was poured into water (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with 1M aqueous hydrochloric acid (50 mL), dried over sodium sulfate and concentrated to afford [ethoxy(methyl)phosphoryl]methyl trifluoromethanesulfonate as light orange oil.
  • 1H NMR (400 MHz, CDCl3) 4.71-4.55 (m, 2H), 4.24-4.10 (m, 2H), 1.68-1.64 (d, 3H), 1.40-1.37 (t, 3H)
    • Step 3: Preparation of 5-[1-[[ethoxy(methyl)phosphoryl]methyl]pyridin-1-ium-4-yl]-1,2,4-thiadiazole trifluoromethanesulfonate A47
  • Figure US20220104493A1-20220407-C00108
  • To a solution of 5-(4-pyridyl)-1,2,4-thiadiazole (1 g) in tetrahydrofuran (20 mL) was added [ethoxy(methyl)phosphoryl]methyl trifluoromethanesulfonate (1.67 g) at room temperature. The resulting mixture was heated at 65° C. for 16 hours. The reaction mixture was concentrated and the residue was dissolved in water (25 mL) and washed with dichloromethane (2×50 mL). The water layer was concentrated and purified by reverse phase HPLC (100% water) to afford 5-[1-[[ethoxy(methyl)phosphoryl]methyl]pyridin-1-ium-4-yl]-1,2,4-thiadiazole trifluoromethanesulfonate as a brown solid.
  • 1H NMR (400 MHz, DMSO-d6) 9.33 (s, 1H), 9.16 (d, 2H), 8.85 (d, 2H), 5.37 (d, 2H), 4.14-4.03 (m, 2H), 1.69 (d, 3H), 1.27-1.19 (m, 3H)
    • Step 4: Preparation of methyl-[[4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]methyl]phosphinate A10
  • To a stirred solution of 5-[1-[[ethoxy(methyl)phosphoryl]methyl]pyridin-1-ium-4-yl]-1,2,4-thiadiazole trifluoromethanesulfonate (0.3 g) in dichloromethane (15 mL) was added bromotrimethylsilane (0.361 g) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by reverse phase HPLC (100% water) to give methyl-[[4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]methyl]phosphinate as a light green gum.
  • 1H NMR (400 MHz, CD3OD) 9.08 (s, 3H), 8.77 (br d, 2H), 5.12 (br s, 2H), 1.71-1.46 (m, 3H)
    • Example 14: Preparation of 3-[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]pyridin-1-ium-1-yl]propane-1-sulfonate A15
  • Figure US20220104493A1-20220407-C00109
  • A mixture of 1,3-propanesultone (0.082 g) and 3-(4-pyridyl)-5-(trifluoromethyl)-1,2,4-oxadiazole (0.095 g) in 1,4-dioxane (2.2 mL) was heated at 100° C. for 20 hours. The resulting precipitate was filtered off and washed with acetone to give 3-[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]pyridin-1-ium-1-yl]propane-1-sulfonate as a colourless solid.
  • 1H NMR (400 MHz, D2O) 9.09 (d, 2H), 8.65 (br d, 2H), 4.78-4.84 (m, 2H), 2.95 (t, 2H), 2.44 (br t, 2H)
    • Example 15: Preparation of 3-[4-[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]pyridin-1-ium-1-yl]propanoic acid acetate A48
  • Figure US20220104493A1-20220407-C00110
  • Step 1: Preparation of ethyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]propanoate
  • Figure US20220104493A1-20220407-C00111
  • To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (3 g) in acetonitrile (60 mL) was added potassium carbonate (5.065 g) followed by ethyl 3-bromopropanoate (1.644 mL). After heating at reflux for 16 hours the mixture was concentrated. The resulting residue was stirred in tert-butyl methyl ether, then filtered. The filtrate was concentrated to give ethyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]propanoate, which was used without further purification.
    • Step 2: Preparation of ethyl 3-[4-[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]-3,6-dihydro-2H-pyridin-1-yl]propanoate
  • Figure US20220104493A1-20220407-C00112
  • A mixture of ethyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]propanoate (0.81 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.175 g), 5-chloro-3-(trifluoromethyl)-1,2,4-thiadiazole (0.45 g), sodium carbonate (1.012 g), 1,4-dioxane (8.35 mL) and water (8.35 mL) was degassed with nitrogen then heated at 120° C. under microwave irradiation for 1 hour. The reaction mixture was cooled to room temperature then filtered through diatomaceous earth. The filtrate was concentrated then purified by silica gel chromatography eluting with a mixture of ethyl acetate in cyclohexane to give ethyl 3-[4-[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]-3,6-dihydro-2H-pyridin-1-yl]propanoate.
    • Step 3: Preparation of 3-[4-[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]pyridin-1-ium-1-yl]propanoic acid acetate A48
  • To a solution of ethyl 3-[4-[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]-3,6-dihydro-2H-pyridin-1-yl]propanoate (0.2 g) in 1,4-dioxane (4.78 mL) was added 1-bromopyrrolidine-2,5-dione (0.19 g). The reaction mixture was stirred at room temperature for 1 hour. To this was added cyclohexane (20 mL) and the mixture was stirred for 10 minutes. The solvent was decanted from a residue, which was washed with ethyl acetate. The residue was purified by preparative reverse phase HPLC to give the ester. The ester was dissolved in 1:1 acetic acid and water and heated at 80° C. for 18 hours. The reaction mixture was concentrated and the residue triturated with acetone to give 3-[4-[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]pyridin-1-ium-1-yl]propanoic acid acetate.
  • 1H NMR (400 MHz, D2O) 9.20 (d, 2H), 8.67 (d, 2H), 4.98 (t, 2H), 3.19 (t, 2H), 2.02 (s, 3H) (CO2H proton missing)
  • Also isolated from this reaction and hydrolysed in a similar way was 3-[3-bromo-4-[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]pyridin-1-ium-1-yl]propanoic acid acetate A79
  • Figure US20220104493A1-20220407-C00113
  • 1H NMR (400 MHz, D2O) 9.68 (s, 1H), 9.21 (dd, 1H), 8.96 (d, 1H), 4.99 (t, 2H), 3.25 (t, 2H), 2.04 (s, 3H) (CO2H proton missing)
    • Example 16: Preparation of 3-[4-(3-hydroxy-1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]propanoic acid bromide A97
  • Figure US20220104493A1-20220407-C00114
    • Step 1: Preparation of 5-(4-pyridyl)-1,2,4-thiadiazol-3-ol
  • Figure US20220104493A1-20220407-C00115
  • To a solution of 3-bromo-5-(4-pyridyl)-1,2,4-thiadiazole (0.25 g) in N,N-dimethylformamide (1.9 mL) was added cesium carbonate (0.673 g) followed by (E)-benzaldehyde oxime (0.126 g). The reaction mixture was heated at 40° C. overnight. It was then heated at 80° C. for 30 hours. The reaction was concentrated and the residue was washed with tert-butyl methyl ether (×3) and dried to give crude 5-(4-pyridyl)-1,2,4-thiadiazol-3-ol, which was used without further purification.
  • 1H NMR (400 MHz, DMSO-d6) 8.63-8.67 (m, 2H), 7.64-7.67 (m, 2H) (OH proton missing)
    • Step 2: Preparation of [5-(4-pyridyl)-1,2,4-thiadiazol-3-yl]-2,2-dimethylpropanoate
  • Figure US20220104493A1-20220407-C00116
  • A solution of 5-(4-pyridyl)-1,2,4-thiadiazol-3-ol (0.05 g) in dichloromethane (2.5 mL) was cooled to ˜0° C. then triethylamine (0.024 mL) and 2,2-dimethylpropanoyl chloride (0.021 mL) were added. The reaction was stirred at ˜0° C. for 2 hours. The reaction mixture was partitioned between water and dichloromethane. The aqueous layer was extracted with further dichloromethane (×2). The combined organic phases were dried over sodium sulfate and concentrated to give [5-(4-pyridyl)-1,2,4-thiadiazol-3-yl]-2,2-dimethylpropanoate, which was used without further purification.
    • Step 3: Preparation of 3-[4-(3-hydroxy-1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]propanoic acid bromide A97
  • A mixture of [5-(4-pyridyl)-1,2,4-thiadiazol-3-yl]-2,2-dimethylpropanoate (0.5 g), acetonitrile (10 mL) and 3-bromopropanoic acid (0.36 g) was heated at 60° C. for 12 hours. The reaction was concentrated and the residue washed with tert-butyl methyl ether and dried to give 3-[4-(3-hydroxy-1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]propanoic acid bromide.
  • 1H NMR (400 MHz, D2O) 9.07 (d, 2H), 8.45 (d, 2H), 4.90 (t, 2H), 3.18 (t, 2H) (CO2H and OH protons missing)
    • Example 17: Preparation of 3-[3-methylsulfonyl-4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]propanoic acid bromide A93
  • Figure US20220104493A1-20220407-C00117
    • Step 1: Preparation of 3-methylsulfonylpyridine-4-carbonitrile
  • Figure US20220104493A1-20220407-C00118
  • To a solution of 3-chloropyridine-4-carbonitrile (0.1 g) in N,N-dimethylformamide (1 mL) was added sodium methanesulfinate (0.174 g) and the mixture was heated at 140° C. for 4 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (20 mL) and water (10 mL). The aqueous layer was extracted with further ethyl acetate (2×20 mL). The combined organic layers were dried over sodium sulfate, concentrated and purified by silica gel chromatography eluting with 0 to 50% ethyl acetate in cyclohexane to give 3-methylsulfonylpyridine-4-carbonitrile as a yellow solid.
  • 1H NMR (400 MHz, CDCl3) 9.30 (br s, 1H), 9.02 (br s, 1H), 7.75 (br s, 1H), 3.25 ppm (br s, 3H)
    • Step 2: Preparation of 3-methylsulfonylpyridine-4-carbothioamide
  • Figure US20220104493A1-20220407-C00119
  • To a solution of 3-methylsulfonylpyridine-4-carbonitrile (1.7 g) in pyridine (1.7 mL) was added triethylamine (1.2 mL) and ammonium polysulfide (48%, 3.4 mL) and the mixture was heated at 60° C. for 2 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (120 mL) and water (30 mL). The aqueous layer was extracted with further ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was triturated with tert-butyl methyl ether (30 mL) to give 3-methylsulfonylpyridine-4-carbothioamide as a light yellow solid.
  • 1H NMR (400 MHz, DMSO-d6) 10.47 (br s, 1H), 10.09 (br s, 1H), 8.99 (s, 1H), 8.85 (d, 1H), 7.39 (d, 1H), 3.47 ppm (s, 3H)
    • Step 3: Preparation of N-(dimethylaminomethylene)-3-methylsulfonyl-pyridine-4-carbothioamide
  • Figure US20220104493A1-20220407-C00120
  • A mixture of 3-methylsulfonylpyridine-4-carbothioamide (1.45 g) and 1,1-dimethoxy-N,N-dimethyl-methanamine (7.25 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated and the residue was triturated with tert-butyl methyl ether (40 mL) and dried to give N-(dimethylaminomethylene)-3-methylsulfonyl-pyridine-4-carbothioamide, which was used without further purification.
    • Step 4: Preparation of 5-(3-methylsulfonyl-4-pyridyl)-1,2,4-thiadiazole
  • Figure US20220104493A1-20220407-C00121
  • To a mixture of N-(dimethylaminomethylene)-3-methylsulfonyl-pyridine-4-carbothioamide (1.52 g), pyridine (0.906 mL) and methanol (15.2 mL), at room temperature, was added a solution of amino hydrogen sulfate (0.697 g) in methanol (7.6 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with sat. aqueous sodium bicarbonate solution and extracted with ethyl acetate (20 mL). The organic layer was dried over sodium sulfate, concentrated and purified by silica gel chromatography eluting with a mixture of ethyl acetate in cyclohexane to give 5-(3-methylsulfonyl-4-pyridyl)-1,2,4-thiadiazole.
  • 1H NMR (400 MHz, CDCl3) 9.45 (s, 1H), 9.04 (d, 1H), 8.84 (s, 1H), 7.62 (d, 1H), 3.46 (s, 3H)
    • Step 5: Preparation of 3-[3-methylsulfonyl-4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]propanoic acid bromide A93
  • A mixture of 5-(3-methylsulfonyl-4-pyridyl)-1,2,4-thiadiazole (0.2 g) and 3-bromopropanoic acid (0.14 g) in acetonitrile (2 mL) was heated at 80° C. for 40 hours. The reaction mixture was concentrated and the residue was triturated with tert-butyl methyl ether (40 mL) and dried to give 3-[3-methylsulfonyl-4-(1,2,4-thiadiazol-5-yl)pyridin-1-ium-1-yl]propanoic acid bromide.
  • 1H NMR (400 MHz, D2O) 9.85 (s, 1H), 9.50 (d, 1H), 9.07 (s, 1H), 8.60 (d, 1H), 5.13 (t, 2H), 3.67 (s, 3H), 3.30 (t, 2H) (CO2H proton missing)
    • Example 18: Preparation of 2-[4-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-1-ium-1-yl]ethanol 2,2,2-trifluoroacetate A69
  • Figure US20220104493A1-20220407-C00122
  • A mixture of 2-phenyl-5-(4-pyridyl)-1,3,4-oxadiazole (0.1 g), 1,2-dichloroethane (6 mL) and 1,3,2-dioxathiolane 2,2-dioxide (0.064 g) was heated at 85° C. overnight. The resulting precipitate is filtered off and the filtrate was concentrated and purified by preparative reverse phase HPLC (trifluoroacetic acid was present in the eluent) to afford 2-[4-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-1-ium-1-yl]ethanol 2,2,2-trifluoroacetate.
  • 1H NMR (400 MHz, DMSO-d6) 9.16-9.33 (m, 2H), 8.75-8.88 (m, 2H), 8.17-8.32 (m, 2H), 7.55-7.80 (m, 3H), 4.68-4.83 (m, 2H), 3.82-4.00 (m, 2H) (OH proton missing)
  • Additional compounds in Table A (below) were prepared by analogues procedures, from appropriate starting materials. The skilled person would understand that the compounds of formula (I) may exist as an agronomically acceptable salt, a zwitterion or an agronomically acceptable salt of a zwitterion as described hereinbefore. Where mentioned the specific counterion is not considered to be limiting, and the compound of formula (I) may be formed with any suitable counter ion.
  • NMR spectra contained herein were recorded on either a 400 MHz Bruker AVANCE III HD equipped with a Bruker SMART probe unless otherwise stated. Chemical shifts are expressed as ppm downfield from TMS, with an internal reference of either TMS or the residual solvent signals. The following multiplicities are used to describe the peaks: s=singlet, d=doublet, t=triplet, dd=double doublet, dt=double triplet, q=quartet, quin=quintet, m=multiplet. Additionally br. is used to describe a broad signal and app. is used to describe and apparent multiplicity.
  • TABLE A
    Physical Data for Compounds of the Invention
    Compound
    Number Structure 1H NMR
    A1
    Figure US20220104493A1-20220407-C00123
         		(400 MHz, D2O) 9.06 (d, 2H), 8.69 (d, 2H), 5.41 (s, 2H) (CO2H proton missing)
    A2
    Figure US20220104493A1-20220407-C00124
         		(400 MHz, D2O) 9.02-9.20 (m, 2H) 8.55-8.68 (m, 2H) 5.58-5.81 (m, 2H) 2.65-2.82 (m, 3H)
    A3
    Figure US20220104493A1-20220407-C00125
         		(400 MHz, D2O) 9.41-9.49 (m, 1H) 8.95-9.04 (m, 2H) 8.37-8.49 (m, 2H) 5.68 (br s, 2H)
    A4
    Figure US20220104493A1-20220407-C00126
         		(400 MHz, D2O) 9.25-9.02 (m, 3H), 8.81-8.66 (m, 2H), 5.85-5.74 (m, 2H)
    A5
    Figure US20220104493A1-20220407-C00127
         		(400 MHz, D2O) 9.02-9.11 (m, 2H) 8.87-8.99 (m, 1H) 8.47-8.60 (m, 2H) 4.94-5.05 (m, 2H) 3.48-3.61 (m, 2H)
    A6
    Figure US20220104493A1-20220407-C00128
         		(400 MHz, D2O) 8.96-8.88 (m, 3H), 8.58-8.54 (m, 2H), 5.40 (s, 2H)
    A7
    Figure US20220104493A1-20220407-C00129
         		(400 MHz, D2O) 9.05 (d, 2H), 8.92 (s, 1H), 8.51 (d, 2H), 4.87 (t, 2H), 3.15 (t, 2H) (CO2H proton missing)
    A8
    Figure US20220104493A1-20220407-C00130
         		(400 MHz, D2O) 9.39-9.45 (m, 1H) 8.85-8.93 (m, 2H) 8.35-8.44 (m, 2H) 5.55 (s, 2H) 3.73-3.84 (m, 3H)
    A9
    Figure US20220104493A1-20220407-C00131
         		(400 MHz, D2O) 9.38-9.43 (m, 1H) 8.83-8.90 (m, 2H) 8.33-8.40 (m, 2H) 5.40 (s, 2H) (CO2H proton missing)
    A10
    Figure US20220104493A1-20220407-C00132
         		(400 MHz, CD3OD) 9.08 (s, 3H), 8.77 (br d, 2H), 5.12 (br s, 2H), 1.71-1.46 (m, 3H)
    A11
    Figure US20220104493A1-20220407-C00133
         		(400 MHz, D2O) 9.13 (d, 2H), 8.98 (s, 1H), 8.62 (d, 2H), 5.86 (d, 1H), 2.02 (d, 3H)
    A12
    Figure US20220104493A1-20220407-C00134
         		(400 MHz, D2O) 9.41 (s, 1H), 9.01 (d, 2H), 8.66 (d, 2H), 4.72-4.79 (m, 2H), 2.99-3.02 (m, 2H), 2.47-2.53 (m, 2H)
    A13
    Figure US20220104493A1-20220407-C00135
         		(400 MHz, D2O) 9.06-9.00 (m, 2H), 8.91 (s, 1H), 8.68 (d, 2H), 5.48 (s, 2H) (CO2H Proton missing)
    A14
    Figure US20220104493A1-20220407-C00136
         		(400 MHz, D2O) 9.08-9.19 (m, 2H), 8.86-8.96 (m, 1H), 8.64 (d, 2H), 4.85- 4.96 (m, 2H), 3.15 (t, 2H) (CO2H proton missing)
    A15
    Figure US20220104493A1-20220407-C00137
         		(400 MHz, D2O) 9.09 (d, 2H), 8.65 (br d, 2H), 4.78-4.84 (m, 2H), 2.95 (t, 2H), 2.44 (br t, 2H)
    A16
    Figure US20220104493A1-20220407-C00138
         		(400 MHz, D2O) 9.17 (s, 1 H), 9.03 (d, 2H), 8.66 (d, 2H), 5.62 (s, 2H), 3.79 (s, 3H)
    A17
    Figure US20220104493A1-20220407-C00139
         		(400 MHz, D2O) 9.15 (d, 1H), 9.09 (d, 2H), 8.61 (br d, 2H), 4.80 (t, 2H), 2.90- 2.98 (m, 2H), 2.39-2.49 (m, 2H)
    A18
    Figure US20220104493A1-20220407-C00140
         		(400 MHz, D2O) 8.89 (br d, 2H), 8.30 (br d, 2H), 2.91 (t, 2H), 2.45-2.34 (m, 2H) (one CH2 underwater peak, oxadiazole proton exchanged)
    A19
    Figure US20220104493A1-20220407-C00141
         		(400 MHz, D2O) 9.35-9.41 (m, 1H), 8.89-8.97 (m, 2H), 8.32 (d, 2H), 4.89- 5.01 (m, 2H), 3.52 (s, 1H), 3.55 (d, 1H)
    A20
    Figure US20220104493A1-20220407-C00142
         		(400 MHz, D2O) 9.08 (d, 2H), 8.66 (d, 2H), 8.63 (s, 1H), 5.75 (s, 2H)
    A21
    Figure US20220104493A1-20220407-C00143
         		(400 MHz, D2O) 9.06 (d, 2H), 8.54- 8.62 (m, 3H), 5.07 (t, 2H), 3.65 (t, 2H)
    A22
    Figure US20220104493A1-20220407-C00144
         		(400 MHz, D2O) 8.95 (d, 2H), 8.62 (t, 3H), 5.40 (s, 2H) (CO2H proton missing)
    A23
    Figure US20220104493A1-20220407-C00145
         		(400 MHz, D2O) 8.98 (d, 2H), 8.54 (d, 2H), 8.18 (d, 1H), 7.54 (d, 1H), 5.65 (s, 2H)
    A24
    Figure US20220104493A1-20220407-C00146
         		(400 MHz, D2O) 8.83 (d, 2H), 8.51 (d, 2H), 8.17 (d, 1H), 8.04 (d, 1H), 5.33 (s, 2H) (CO2H proton missing)
    A25
    Figure US20220104493A1-20220407-C00147
         		(400 MHz, D2O) 8.95 (d, 2H), 8.46 (d, 2H), 8.14 (d, 1H), 8.01 (d, 1H), 4.86 (t, 2H), 3.18 (t, 2H) (CO2H proton missing)
    A26
    Figure US20220104493A1-20220407-C00148
         		(400 MHz, D2O) 9.04-9.21 (m, 2H), 8.43-8.55 (m, 2H), 5.00-5.13 (m, 2H), 4.23-4.35 (m, 3H), 3.49-3.68 (m, 2H)
    A27
    Figure US20220104493A1-20220407-C00149
         		(400 MHz, D2O) 8.97-9.10 (m, 2H), 8.54-8.66 (m, 2H), 4.95-5.06 (m, 2H), 4.41-4.53 (m, 3H), 3.50-3.63 (m, 2H)
    A28
    Figure US20220104493A1-20220407-C00150
         		(400 MHz, D2O) 9.03-8.90 (m, 3H), 8.52 (d, 2H), 5.39-5.32 (m, 1H), 1.84 (d, 3H) (CO2H proton missing)
    A29
    Figure US20220104493A1-20220407-C00151
         		(400 MHz, D2O) 8.96 (s, 1H), 8.92 (d, 2H), 8.59 (d, 2H), 5.52 (s, 2H), 3.17 (s, 3H)
    A30
    Figure US20220104493A1-20220407-C00152
         		(400 MHz, D2O) 8.96-8.88 (m, 3H), 8.54 (d, 2H), 4.90-4.83 (m, 2H), 3.54 (d, 3H)
    A31
    Figure US20220104493A1-20220407-C00153
         		(400 MHz, D2O) 8.95-8.87 (m, 3H), 8.56-8.51 (m, 2H), 4.86-4.79 (m, 2H), 3.90-3.82 (m, 2H), 1.12 (t, 3H)
    A32
    Figure US20220104493A1-20220407-C00154
         		(400 MHz, D2O) 9.01-8.86 (m, 3H), 8.54 (d, 2H), 4.84-4.78 (m, 2H) (POH proton missing)
    A33
    Figure US20220104493A1-20220407-C00155
         		(400 MHz, D2O) 9.03 (d, 2H), 8.50 (d, 2H), 5.44 (s, 2H), 4.28 (s, 3H) (CO2H proton missing)
    A34
    Figure US20220104493A1-20220407-C00156
         		(400 MHz, D2O) 8.91-8.85 (m, 2H), 8.63-8.59 (m, 2H), 5.35 (s, 2H), 4.44 (s, 3H) (CO2H proton missing)
    A35
    Figure US20220104493A1-20220407-C00157
         		(400 MHz, D2O) 9.13-9.05 (m, 2H), 8.78-8.67 (m, 2H), 5.77-5.70 (m, 2H), 4.56-4.48 (m, 3H)
    A36
    Figure US20220104493A1-20220407-C00158
         		(400 MHz, D2O) 9.05 (d, 2H), 8.52 (d, 2H), 4.78 (t, 2H), 2.94 (t, 2H), 2.63 (s, 3H), 2.43 (t, 2H)
    A37
    Figure US20220104493A1-20220407-C00159
         		(400 MHz, D2O) 9.02 (d, 2H), 8.67 (s, 1H), 8.43 (d, 2H), 7.39 (d, 1H), 4.90 (t, 2H), 3.20 (t, 2H) (CO2H proton missing)
    A38
    Figure US20220104493A1-20220407-C00160
         		(400 MHz, D2O) 9.14 (d, 2H), 8.63 (d, 2H), 5.06 (t, 2H), 3.60 (t, 2H)
    A39
    Figure US20220104493A1-20220407-C00161
         		(400 MHz, D2O) 8.97 (d, 2H), 8.47 (d, 2H), 8.14 (d, 1H), 7.50 (d, 1H), 3.55 (t, 2H) 4.97 (t, 2H)
    A40
    Figure US20220104493A1-20220407-C00162
         		(400 MHz, D2O) 8.89 (d, 2H), 8.67 (d, 1H), 8.46 (d, 2H), 7.42 (d, 1H), 5.37 (s, 2H) (CO2H proton missing)
    A41
    Figure US20220104493A1-20220407-C00163
         		(400 MHz, D2O) 9.03 (d, 2H), 8.67 (d, 1H), 8.45 (d, 2H), 7.41 (d, 1H), 5.01- 5.07 (m, 2H), 3.60-3.64 (m, 2H)
    A42
    Figure US20220104493A1-20220407-C00164
         		(400 MHz, DMSO-d6) 9.39 (d, 1H), 9.08 (d, 2H), 8.72 (d, 2H), 8.37 (d, 1H), 5.45 (s, 2H)
    A43
    Figure US20220104493A1-20220407-C00165
         		(400 MHz, D2O) 9.13 (d, 2H), 8.75 (d, 1H), 8.66 (d, 2H), 5.75 (s, 2H)
    A44
    Figure US20220104493A1-20220407-C00166
         		(400 MHz, D2O) 8.97 (d, 2H), 8.70- 8.76 (m, 1H), 8.60 (d, 2H), 5.38 (s, 2H) (CO2H proton missing)
    A45
    Figure US20220104493A1-20220407-C00167
         		(400 MHz, D2O) 9.11 (d, 2H), 8.65- 8.79 (m, 1H), 8.56 (d, 2H), 4.93 (t, 2H) 3.20 (t, 2H) (CO2H proton missing)
    A46
    Figure US20220104493A1-20220407-C00168
         		(400 MHz, D2O) 9.09 (d, 2H), 8.71 (d, 1H), 8.57 (d, 2H), 5.11-5.02 (m, 2H), 3.56-3.66 (m, 2H)
    A47
    Figure US20220104493A1-20220407-C00169
         		(400 MHz, DMSO-d6) 9.33 (s, 1H), 9.16 (d, 2H), 8.85 (d, 2H), 5.37 (d, 2H), 4.14-4.03 (m, 2H), 1.69 (d, 3H), 1.27- 1.19 (m, 3H)
    A48
    Figure US20220104493A1-20220407-C00170
         		(400 MHz, D2O) 9.20 (d, 2H), 8.67 (d, 2H), 4.98 (t, 2H), 3.19 (t, 2H), 2.02 (s, 3H) (CO2H proton missing)
    A49
    Figure US20220104493A1-20220407-C00171
         		(400 MHz, DMSO-d6) 9.71 (s, 1H), 9.25 (d, 2H), 8.81 (d, 2H), 5.75 (s, 2H), 4.27 (q, 2H), 1.27 (t, 3H)
    A50
    Figure US20220104493A1-20220407-C00172
         		(400 MHz, D2O) 9.14 (d, 2H), 8.58 (d, 2H), 4.91 (t, 2H), 3.16 (t, 2H), 2.45 (s, 3H) (CO2H proton missing)
    A51
    Figure US20220104493A1-20220407-C00173
         		(400 MHz, D2O) 9.06 (d, 2H), 8.64 (d, 2H), 4.80 (t, 2H), 2.97-2.90 (m, 5H), 2.49-2.39 (m, 2H) (NH proton missing)
    A52
    Figure US20220104493A1-20220407-C00174
         		(400 MHz, D2O) 8.88-9.03 (m, 2H), 8.36-8.48 (m, 2H), 7.53-7.66 (m, 1H), 4.64-4.82 (m, 2H), 2.93 (t, 2H), 2.87 (s, 3H), 2.42 (quin, 2H) (NH proton missing)
    A53
    Figure US20220104493A1-20220407-C00175
         		(400 MHz, D2O) 9.80 (s, 1H), 8.84 (d, 2H), 8.62 (d, 2H), 5.39 (s, 2H) (CO2H proton missing)
    A54
    Figure US20220104493A1-20220407-C00176
         		(400 MHz, DMSO-d6) 10.32 (s, 1H), 9.09-9.20 (m, 2H), 8.88 (d, 2H), 5.43- 5.52 (m, 2H)
    A55
    Figure US20220104493A1-20220407-C00177
         		(400 MHz, D2O) 9.34-9.45 (m, 1H), 8.94-9.10 (m, 2H), 8.74-8.83 (m, 1H), 4.88-5.03 (m, 2H), 3.11-3.25 (m, 2H) (CO2H proton missing)
    A56
    Figure US20220104493A1-20220407-C00178
         		(400 MHz, D2O) 9.40-9.52 (m, 1H), 8.98-9.11 (m, 2H), 8.82-8.92 (m, 1H), 4.87-4.96 (m, 2H), 3.08-3.26 (m, 2H) (CO2H proton missing)
    A57
    Figure US20220104493A1-20220407-C00179
         		(400 MHz, DMSO-d6) 9.34-9.15 (m, 2H), 8.78-8.60 (m, 2H), 5.59 (br s, 2H), 4.37 (br s, 3H)
    A58
    Figure US20220104493A1-20220407-C00180
         		(400 MHz, D2O) 9.07 (d, 2H), 8.94 (s, 1H), 8.54 (d, 2H), 4.90 (t, 2H), 3.60 (s, 3H), 3.18 (t, 2H)
    A59
    Figure US20220104493A1-20220407-C00181
         		(400 MHz, D2O) 8.93-8.89 (m, 2H), 8.51-8.46 (m, 2H), 5.37 (s, 2H), 2.67 (s, 3H) (CO2H proton missing)
    A60
    Figure US20220104493A1-20220407-C00182
         		(400 MHz, DMSO-d6) 9.18-9.10 (m, 2H), 8.69 (d, 2H), 8.21 (s, 1H), 8.01 (d, 2H), 7.61-7.47 (m, 3H), 4.91-4.82 (m, 2H), 4.34-4.21 (m, 2H)
    A61
    Figure US20220104493A1-20220407-C00183
         		(400 MHz, DMSO-d6) 10.02 (s. 1H), 9.28-9.19 (m, 2H), 8.72 (br d, 2H), 4.99-4.88 (m, 2H), 4.28 (br s, 2H)
    A62
    Figure US20220104493A1-20220407-C00184
         		(400 MHz, DMSO-d6) 14.94 (br s, 1H), 9.07 (d, 2H), 8.93 (s, 1H), 8.60 (d, 2H), 4.90-4.77 (m, 2H), 4.30-4.19 (m, 2H)
    A63
    Figure US20220104493A1-20220407-C00185
         		(400 MHz, DMSO-d6) 8.94-9.08 (m, 2H), 8.79-8.90 (m, 1H), 8.47-8.61 (m, 2H), 4.69-4.85 (m, 2H), 4.14- 4.31 (m, 2H), 2.69-2.84 (m, 3H)
    A64
    Figure US20220104493A1-20220407-C00186
         		(400 MHz, DMSO-d6) 9.60-9.79 (m, 1H), 9.17-9.31 (m, 2H), 8.64-8.81 (m, 2H), 4.83-5.02 (m, 2H), 4.19- 4.36 (m, 2H)
    A65
    Figure US20220104493A1-20220407-C00187
         		(400 MHz, DMSO-d6) 10.23-10.36 (m, 1H), 9.09-9.24 (m, 2H), 8.73- 8.96 (m, 2H), 4.73-4.94 (m, 2H), 4.18- 4.34 (m, 2H)
    A66
    Figure US20220104493A1-20220407-C00188
         		(400 MHz, DMSO-d6) 9.16 (d, 2H), 8.56 (d, 2H), 7.61-7.57 (m, 1H), 4.89- 4.78 (m, 2H), 4.32-4.19 (m, 2H), 2.39 (s, 3H)
    A67
    Figure US20220104493A1-20220407-C00189
         		(400 MHz, DMSO-d6) 8.95 (d, 2H), 8.76-8.91 (m, 1H), 8.36 (d, 2H), 7.98 (s, 1H), 7.22-7.41 (m, 1H), 4.61-4.84 (m, 2H), 4.12-4.34 (m, 2H)
    A68
    Figure US20220104493A1-20220407-C00190
         		(400 MHz, DMSO-d6) 8.83-9.01 (m, 2H), 8.24-8.36 (m, 2H), 8.13-8.23 (m, 1H), 7.75-7.90 (m, 1H), 6.89 (dd, 1H), 4.62-4.87 (m, 2H), 4.08-4.30 (m, 2H)
    A69
    Figure US20220104493A1-20220407-C00191
         		(400 MHz, DMSO-d6) 9.16-9.33 (m, 2H), 8.75-8.88 (m, 2H), 8.17-8.32 (m, 2H), 7.55-7.80 (m, 3H), 4.68- 4.83 (m, 2H), 3.82-4.00 (m, 2H) (OH proton missing)
    A70
    Figure US20220104493A1-20220407-C00192
         		(400 MHz, D2O) 9.45 (s, 1H), 9.08 (d, 2H) 8.65 (d, 2H), 4.80-4.83 (m, 2H), 2.98 (t, 2H), 2.48-2.53 (m, 2H)
    A71
    Figure US20220104493A1-20220407-C00193
         		(400 MHz, D2O) 9.09 (d, 2H) 8.60 (d, 2H), 4.83-4.87 (m, 2H), 3.01 (t, 2H), 2.74 (s, 3H), 2.49-2.53 (m, 2H)
    A72
    Figure US20220104493A1-20220407-C00194
         		(400 MHz, D2O) 9.07 (d, 2H) 8.61 (d, 2H), 4.98-5.02 (m, 2H), 4.53-4.56 (m, 2H), 2.74 (s, 3H)
    A73
    Figure US20220104493A1-20220407-C00195
         		(400 MHz, DMSO-d6) 9.02-9.13 (m, 2H), 8.32-8.45 (m, 2H), 7.60-7.73 (m, 1H), 6.89-7.14 (m, 1H), 4.63- 4.75 (m, 2H), 4.04-4.17 (m, 2H), 3.82- 3.97 (m, 3H) (OH proton missing)
    A74
    Figure US20220104493A1-20220407-C00196
         		(400 MHz, DMSO-d6) 8.99-9.16 (m, 2H), 8.30-8.45 (m, 2H), 7.61-7.70 (m, 1H), 7.02-7.13 (m, 1H), 4.78- 4.91 (m, 2H), 4.22-4.33 (m, 2H), 4.05-4.16 (m, 3H)
    A75
    Figure US20220104493A1-20220407-C00197
         		(400 MHz, D2O) 9.12 (d, 2H), 9.02 (s, 1H), 8.65 (d, 2H), 5.83 (q, 1H), 3.80 (s, 3H), 1.99 (d, 3H)
    A76
    Figure US20220104493A1-20220407-C00198
         		(400 MHz, DMSO-d6) 9.33 (s, 1H), 9.18 (br d, 2H), 8.87 (d, 2H), 5.54- 5.46 (m, 2H), 4.21-4.10 (m, 4H), 1.28- 1.19 (m, 6H)
    A77
    Figure US20220104493A1-20220407-C00199
         		(400 MHz, DMSO-d6) 9.33 (s, 1H), 9.22-9.17 (m, 2H), 8.88-8.83 (m, 2H), 5.54 (d, 2H), 3.83-3.76 (m, 6H)
    A78
    Figure US20220104493A1-20220407-C00200
         		(400 MHz, D2O) 8.64 (d, 2H), 8.19 (d, 2H), 7.79 (d, 1H), 6.98 (d, 1H), 5.34 (s, 2H) (CO2H and NH protons missing)
    A79
    Figure US20220104493A1-20220407-C00201
         		(400 MHz, D2O) 9.68 (s, 1H), 9.21 (dd, 1H), 8.96 (d, 1H), 4.99 (t, 2H), 3.25 (t, 2H), 2.04 (s, 3H) (CO2H proton missing)
    A80
    Figure US20220104493A1-20220407-C00202
         		(400 MHz, D2O) 9.15 (d, 1H), 8.87 (d, 2H), 8.60 (d, 2H), 8.12 (d, 1H), 5.46 (s, 2H), 1.48 (s, 9H)
    A81
    Figure US20220104493A1-20220407-C00203
         		(400 MHz, D2O) 9.10 (d, 1H), 8.82 (d, 2H), 8.53 (d, 2H), 8.07 (d, 1H), 5.37 (s, 2H) (CO2H proton missing)
    A82
    Figure US20220104493A1-20220407-C00204
         		(400 MHz, D2O) 9.02 (d, 2H), 8.66 (d, 1H), 8.50 (d, 2H), 7.43 (d, 1H), 5.69 (s, 2H)
    A83
    Figure US20220104493A1-20220407-C00205
         		(400 MHz, D2O) 10.33 (s, 1H), 8.93 (d, 2H), 8.81 (d, 2H), 5.36 (s, 2H) (CO2H proton missing)
    A84
    Figure US20220104493A1-20220407-C00206
         		(400 MHz, D2O) 9.02 (d, 2H), 8.62 (d, 2H), 8.25 (d, 1H), 8.13 (d, 1H), 5.73 (s, 2H)
    A85
    Figure US20220104493A1-20220407-C00207
         		(400 MHz, D2O) 9.25 (d, 2H), 8.81 (d, 2H), 5.84 (s, 2H)
    A86
    Figure US20220104493A1-20220407-C00208
         		(400 MHz, D2O) 8.87 (d, 2H), 8.68 (d, 1H), 8.36 (d, 2H), 8.05 (d, 1H), 5.44 (s, 2H) (CO2H proton missing)
    A87
    Figure US20220104493A1-20220407-C00209
         		(400 MHz, D2O) 8.99 (d, 2H), 8.71 (d, 1H), 8.42 (d, 2H), 8.10 (d, 1H), 5.71 (s, 2H)
    A88
    Figure US20220104493A1-20220407-C00210
         		(400 MHz, D2O) 9.08 (d, 2H), 8.86 (s, 1H), 8.59 (d, 2H), 4.93 (t, 2H), 3.22 (t, 2H) (CO2H proton missing)
    A89
    Figure US20220104493A1-20220407-C00211
         		(400 MHz, D2O) 9.17 (d, 2H), 8.63 (d, 2H), 4.95 (t, 2H), 3.21 (t, 2H) (CO2H proton missing)
    A90
    Figure US20220104493A1-20220407-C00212
         		(400 MHz, D2O) 9.05 (d, 2H), 8.52 (d, 2H), 5.70 (s, 2H) (NH protons missing)
    A91
    Figure US20220104493A1-20220407-C00213
         		(400 MHz, D2O) 9.20 (d, 2H), 8.69 (d, 2H), 5.12 (t, 2H), 3.66 (t, 2H)
    A92
    Figure US20220104493A1-20220407-C00214
         		(400 MHz, D2O) 9.04 (d, 2H), 8.44 (d, 2H), 4.89 (t, 2H), 3.16 (t, 2H) (CO2H and NH protons missing)
    A93
    Figure US20220104493A1-20220407-C00215
         		(400 MHz, D2O) 9.85 (s, 1H), 9.50 (d, 1H), 9.07 (s, 1H), 8.60 (d, 1H), 5.13 (t, 2H), 3.67 (s, 3H), 3.30 (t, 2H) (CO2H proton missing)
    A94
    Figure US20220104493A1-20220407-C00216
         		(400 MHz, D2O) 8.88 (d, 2H), 8.36 (d, 2H), 5.49 (s, 2H) (CO2H and NH protons missing)
    A95
    Figure US20220104493A1-20220407-C00217
         		(400 MHz, D2O) 8.92 (d, 2H), 8.53 (d, 2H), 5.38 (s, 2H), 2.87 (s, 3H) (CO2H proton missing)
    A96
    Figure US20220104493A1-20220407-C00218
         		(400 MHz, D2O) 9.16 (d, 2H), 8.66 (d, 2H), 5.77 (s, 2H)
    A97
    Figure US20220104493A1-20220407-C00219
         		(400 MHz, D2O) 9.07 (d, 2H), 8.45 (d, 2H), 4.90 (t, 2H), 3.18 (t, 2H) (CO2H and OH protons missing)
    A98
    Figure US20220104493A1-20220407-C00220
         		(400 MHz, D2O) 8.90 (d, 2H), 8.46 (d, 2H), 5.33 (s, 2H) (CO2H and OH protons missing)
    A99
    Figure US20220104493A1-20220407-C00221
         		(400 MHz, D2O) 9.08 (d, 2H) 8.56 (d, 2H) 5.72 (s, 2H) (OH proton missing)
    A100
    Figure US20220104493A1-20220407-C00222
         		(400 MHz, D2O) 9.02 (d, 2H), 8.62 (d, 2H), 8.25 (d, 1H), 8.13 (d, 1H), 5.73 (s, 2H)
    A101
    Figure US20220104493A1-20220407-C00223
         		(400 MHz, D2O) 9.84 (s, 1H), 8.87 (d, 2H), 8.67 (d, 2H), 5.55 (s, 2H), 3.79 (s, 3H)
    • BIOLOGICAL EXAMPLES Post-Emergence Efficacy Method A
  • Seeds of a variety of test species were sown in standard soil in pots. After cultivation for 14 days (post-emergence) under controlled conditions in a glasshouse (at 24/16° C., day/night; 14 hours light; 65% humidity), the plants were sprayed with an aqueous spray solution derived from the dissolution of the technical active ingredient formula (I) in a small amount of acetone and a special solvent and emulsifier mixture referred to as IF50 (11.12% Emulsogen EL360 TM+44.44% N-methylpyrrolidone+44.44% Dowanol DPM glycol ether), to create a 50 g/l solution which was then diluted to required concentration using 0.25% or 1% Empicol ESC70 (Sodium lauryl ether sulphate)+1% ammonium sulphate as diluent. The test plants were then grown in a glasshouse under controlled conditions (at 24/16° C., day/night; 14 hours light; 65% humidity) and watered twice daily. After 13 days the test was evaluated (100=total damage to plant; 0=no damage to plant).
    • Method B
  • Seeds of a variety of test species were sown in standard loam based soil in pots. Plants were cultivated from between 21 and 28 days (post-emergence) under controlled conditions in a glasshouse (at 24/16° C., day/night; 14 hours light; 65% humidity) for warm climate species and (at 20/16° C. day/night; 15 hours light; 65% humidity) for cool climate species.
  • The plants were sprayed with an aqueous spray solution derived from dissolving the technical active ingredient formula in a small amount of acetone and a special solvent and emulsifier mixture referred to as IF50 (11.12% Emulsogen EL360 TM+44.44% N-methylpyrrolidone+44.44% Dowanol DPM glycol ether), to create a 50 g/l solution which was then diluted to required concentration using 0.5% or 1% Empicol ESC70 (Sodium lauryl ether sulphate)+1% ammonium sulphate as diluent.
  • The delivery of the aqueous spray solution was via a laboratory track sprayer which delivered the aqueous spray composition at a rate of 200 litres per hectare, using a flat fan nozzle (Teejet 11002VS) and an application volume of 200 litre/ha (at 2 bar).
  • The test plants were then grown in a glasshouse under controlled conditions (at 24/16° C., day/night; 14 hours light; 65% humidity) for warm climate species and (at 20/16° C. day/night; 15 hours light; 65% humidity) for cool climate species and watered twice daily. After 7 and 14 days the test was evaluated (100=total damage to plant; 0=no damage to plant).
  • The results from method A are shown in Table B (below). A value of n/a indicates that this combination of weed and test compound was not tested/assessed.
    • Test Plants for Method A:
  • Ipomoea hederacea (IPOHE), Euphorbia heterophylla (EPHHL), Chenopodium album (CHEAL), Amaranthus palmeri (AMAPA), Lolium perenne (LOLPE), Digitaria sanguinalis (DIGSA), Eleusine indica (ELEIN), Echinochloa crus-galli (ECHCG), Setaria faberi (SETFA)
    • Test Plants for Method B:
  • Brassica napus (BRSNN), Solanum turberosum (SOLTU), Glycine Max (GLXMA), and Helianthus annus (HELAN)
  • TABLE B
    Control of weed species by compounds of formula (I) after post-emergence application
    Compound Application
    Number Rate g/Ha AMAPA CHEAL EPHHL IPOHE ELEIN LOLPE DIGSA SETFA ECHCG
    A1 500 100 90 n/a 40 90 70 70 90 60
    A2 500 100 90 n/a 70 80 60 90 70 60
    A3 500 100 90 80 80 50 20 70 80 40
    A4 500 100 100 100 100 80 80 70 80 70
    A5 500 100 90 100 70 80 70 70 60 40
    A6 500 100 100 100 80 90 30 70 80 90
    A7 500 100 90 80 30 70 30 90 70 50
    A8 500 n/a 70 60 10 30 0 50 30 20
    A9 500 30 0 10 20 n/a 0 n/a 0 n/a
    A10 500 90 90 n/a 50 90 40 90 100 90
    A11 500 100 90 n/a 80 90 60 80 60 100
    A12 1000 0 0 20 0 20 10 20 0 0
    A13 500 100 50 70 30 50 10 60 70 50
    A14 500 100 70 30 20 40 10 50 60 50
    A15 500 0 0 n/a 20 10 0 30 30 30
    A16 500 0 0 20 20 10 0 40 30 20
    A17 500 70 70 50 20 10 0 40 40 30
    A18 500 100 50 50 20 30 10 30 40 50
    A19 500 100 50 50 50 30 30 30 40 40
    A21 500 70 0 n/a 10 80 20 70 70 90
    A22 500 10 10 40 0 n/a 0 n/a 0 n/a
    A23 500 0 20 n/a 10 0 0 20 0 0
    A24 500 0 40 40 20 0 0 10 0 0
    A25 500 0 10 0 10 10 0 10 0 0
    A26 500 0 10 20 10 10 10 20 10 10
    A27 500 10 10 20 10 0 0 0 0 0
    A28 500 100 80 20 70 n/a 30 n/a 80 n/a
    A29 500 90 30 n/a 90 50 40 90 50 90
    A30 500 90 70 n/a 50 90 30 90 90 90
    A31 500 70 70 n/a 30 80 20 80 40 70
    A32 500 60 20 n/a 0 40 10 50 20 70
    A33 500 90 40 40 0 20 0 20 0 0
    A34 500 70 0 0 0 0 0 0 0 0
    A35 500 70 60 50 40 20 n/a 20 30 40
    A36 500 70 60 60 30 10 0 30 10 10
    A38 500 90 60 n/a 60 80 70 50 40 60
    A39 500 40 30 n/a 20 0 0 0 0 0
    A40 500 10 0 n/a 20 0 0 0 0 0
    A41 500 10 0 n/a 0 0 0 10 10 10
    A42 500 90 20 n/a 10 0 0 10 10 10
    A43 500 40 40 n/a 30 60 10 30 20 60
    A44 500 30 10 n/a 0 10 10 20 0 10
    A45 500 0 0 n/a 0 50 0 20 0 10
    A46 500 30 0 0 0 0 0 0 0 0
    A47 500 60 60 10 10 10 0 10 10 10
    A48 125 90 10 30 0 0 10 0 20 0
    A49 500 10 50 n/a 10 20 20 50 20 10
    A50 500 40 70 n/a 30 40 50 90 80 20
    A51 500 10 60 n/a 10 10 20 50 30 30
    A52 500 20 30 n/a 10 10 10 20 10 10
    A53 500 10 10 20 20 0 0 0 10 10
    A54 500 20 20 n/a 20 20 0 10 0 0
    A55 500 50 40 10 30 n/a 30 n/a 20 n/a
    A56 500 60 30 100 30 n/a 10 n/a 30 n/a
    A57 500 100 80 20 0 20 0 30 0 60
    A64 500 50 30 30 20 20 10 30 20 50
    A65 500 30 20 20 20 20 10 30 10 20
    A69 500 20 30 20 20 30 10 10 10 20
    A71 500 20 50 40 30 20 0 30 10 20
    A74 500 10 40 20 10 20 10 30 20 20
    A79 500 90 40 60 40 90 30 80 70 80
    A81 500 70 40 20 0 40 0 10 10 10
    A83 500 20 30 50 10 10 10 20 10 0
    A84 500 70 60 50 10 50 10 10 10 30
    A85 500 100 90 100 100 100 90 100 100 100
    A86 500 40 10 40 10 20 0 10 10 20
    A87 500 0 10 20 0 0 0 0 20 20
    A88 500 10 20 90 0 0 0 0 0 0
    A89 500 30 30 20 10 80 10 90 80 60
    A90 500 100 80 90 50 90 60 90 60 50
    A92 500 100 60 80 20 20 10 80 60 60
    A93 500 60 30 30 30 30 10 n/a 30 40
    A94 500 30 40 30 10 40 10 30 10 20
    A95 500 40 30 10 10 60 0 10 10 20
    A96 500 100 100 100 30 90 100 100 80 100
    A97 500 0 50 10 10 10 10 0 10 0
    A98 500 50 40 30 10 10 0 70 20 40
    A100 500 70 60 50 10 50 10 10 10 30
  • The results from method B are shown in Table C (below). A value of n/a indicates that this combination of weed and test compound was not tested/assessed.
  • TABLE C
    Control of weed species by compounds of formula (I) after
    post-emerdence application
    Compound Application
    Number Rate g/Ha BRSNN SOLTU GLXMA HELAN
    A4 50 23 15 45
    A4 150 32 30 83
    A4 600 43 82 93
    A4 50 43 50 52 97
    A4 150 57 60 62 100
    A4 600 80 67 85 100

Claims (19)

1. A method of controlling unwanted plant growth, comprising applying a compound of formula (I):
Figure US20220104493A1-20220407-C00224
wherein
R1 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C1-C6haloalkyl, —OR7, —OR15a, —N(R6)S(O)2R15, —N(R6)C(O)R15, —N(R6)C(O)OR15, —N(R6)C(O)NR16R17, —N(R6)CHO, —N(R7a)2 and —S(O)rR15;
R2 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl and C1-C6haloalkyl;
and wherein when R1 is selected from the group consisting of —OR7, —OR15a, —N(R6)S(O)2R15, —N(R6)C(O)R15, —N(R6)C(O)OR15, —N(R6)C(O)NR16R17, —N(R6)CHO, —N(R7a)2 and —S(O)rR15, R2 is selected from the group consisting of hydrogen and C1-C6alkyl; or
R1 and R2 together with the carbon atom to which they are attached form a C3-C6cycloalkyl ring or a 3- to 6-membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O; and
Q is (CR1aR2b)m;
m is 0, 1, 2 or 3;
each R1a and R2b are independently selected from the group consisting of hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, —OH, —OR7, —OR15a —NH2—NHR7, —NHR15a, —N(R6)CHO, —NR7bR7c and —S(O)rR15; or
each R1a and R2b together with the carbon atom to which they are attached form a C3-C6cycloalkyl ring or a 3- to 6-membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O; and
R3, R3a, R4 and R5 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, —S(O)rR15, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6fluoroalkoxy, C1-C6alkoxy, C3-C6cycloalkyl and —N(R6)2;
each R6 is independently selected from hydrogen and C1-C6alkyl;
each R7 is independently selected from the group consisting of C1-C6alkyl, —S(O)2R15, —C(O)R15, —C(O)OR15 and —C(O)NR16R17;
each R7a is independently selected from the group consisting of —S(O)2R15, —C(O)R15, —C(O)OR15, —C(O)NR16R17 and —C(O)NR6R15a;
R7b and R7c are independently selected from the group consisting of C1-C6alkyl, —S(O)2R15, —C(O)R15, —C(O)OR15, —C(O)NR16R17 and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R9 substituents, which may be the same or different; or
R7b and R7c together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S; and
A is a 5-membered heteroaryl attached to the rest of the molecule via a ring carbon atom, which comprises 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S, and wherein the heteroaryl may, where feasible, be optionally substituted by 1, 2 or 3 R8 substituents, which may be the same or different, and wherein when A is substituted on one or more ring carbon atoms, each R8 is independently selected from the group consisting of halogen, nitro, cyano, —NH2, —NHR7, —N(R7)2, —OH, —OR7, —S(O)rR15, —NR6S(O)2R15, —C(O)OR10, —C(O)R15, —C(O)NR16R17, —S(O)2NR16R17, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C3-C6halocycloalkyl, C3-C6cycloalkoxy, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, C1-C3alkoxyC1-C3alkyl-, hydroxyC1-C6alkyl-, C1-C3alkoxyC1-C3alkoxy-, C1-C6haloalkoxy, C1-C3haloalkoxyC1-C3alkyl-, C3-C6alkenyloxy, C3-C6alkynyloxy, N—C3-C6cycloalkylamino, —C(R6)═NOR6, phenyl, a 3- to 6-membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O, and a 5- or 6-membered heteroaryl, which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, and wherein said phenyl, heterocyclyl or heteroaryl are optionally substituted by 1, 2 or 3 R9 substituents, which may be the same or different;
and/or
when A is substituted on a ring nitrogen atom, R8 is selected from the group consisting of —OR7, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C3-C6halocycloalkyl, C3-C6cycloalkoxy, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, C1-C3alkoxyC1-C3alkyl-, hydroxyC1-C6alkyl-, C1-C3alkoxyC1-C3alkoxy-, C1-C6haloalkoxy, C1-C3haloalkoxyC1-C3alkyl-, C3-C6alkenyloxy and C3-C6alkynyloxy; and
each R9 is independently selected from the group consisting of halogen, cyano, —OH, —N(R6)2, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl and C1-C4haloalkoxy;
X is selected from the group consisting of C3-C6cycloalkyl, phenyl, a 5- or 6-membered heteroaryl, which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, and a 4- to 6-membered heterocyclyl, which comprises 1, 2 or 3 heteroatoms individually selected from N, O and S, and wherein said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties are optionally substituted by 1 or 2 R9 substituents, and wherein the aforementioned CR1R2, Q and Z moieties may be attached at any position of said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties;
n is 0 or 1;
Z is selected from the group consisting of —C(O)OR10, —CH2OH, —CHO, —C(O)NHOR11, —C(O)NHCN, —OC(O)NHOR11, —OC(O)NHCN, —NR6C(O)NHOR11, —NR6C(O)NHCN, —C(O)NHS(O)2R12, —OC(O)NHS(O)2R12, —NR6C(O)NHS(O)2R12, —S(O)2OR10, —OS(O)2OR10, —NR6S(O)2OR10, —NR6S(O)OR10, —NHS(O)2R14, —S(O)OR10, —OS(O)OR10, —S(O)2NHCN, —S(O)2NHC(O)R18, —S(O)2NHS(O)2R12, —OS(O)2NHCN, —OS(O)2NHS(O)2R12, —OS(O)2NHC(O)R18, —NR6S(O)2NHCN, —NR6S(O)2NHC(O)R18, —N(OH)C(O)R15, —ONHC(O)R15, —NR6S(O)2NHS(O)2R12, —P(O)(R13)(OR10), —P(O)H(OR10), —OP(O)(R13)(OR10), —NR6P(O)(R13)(OR10) and tetrazole;
R10 is selected from the group consisting of hydrogen, C1-C6alkyl, phenyl and benzyl, and wherein said phenyl or benzyl are optionally substituted by 1, 2 or 3 R9 substituents, which may be the same or different;
R11 is selected from the group consisting of hydrogen, C1-C6alkyl and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R9 substituents, which may be the same or different;
R12 is selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, —OH, —N(R6)2 and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R9 substituents, which may be the same or different;
R13 is selected from the group consisting of —OH, C1-C6alkyl, C1-C6alkoxy and phenyl;
R14 is C1-C6haloalkyl;
R15 is selected from the group consisting of C1-C6alkyl and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R9 substituents, which may be the same or different;
R15a is phenyl, wherein said phenyl is optionally substituted by 1, 2 or 3 R9 substituents, which may be the same or different;
R16 and R17 are independently selected from the group consisting of hydrogen and C1-C6alkyl; or
R16 and R17 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S; and
R18 is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, —N(R6)2 and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R9 substituents, which may be the same or different;
and
r is 0, 1 or 2,
to the unwanted plants or to the locus thereof.
2. A compound of formula (I) or an agronomically acceptable salt or zwitterionic species thereof, as defined in claim 1, with the proviso that:
i) in the compound of formula (I), A is not selected from the group consisting of formula A-Ib to A-IIIb below
Figure US20220104493A1-20220407-C00225
wherein each R8b′ is independently selected from the group consisting of phenyl, 4-methoxyphenyl, 4-butoxyphenyl, 4-fluorophenyl and methoxy, and each R8c′, is independently hydrogen or methyl;
or
ii) the compound of formula (I) is not selected from the group consisting of:
Figure US20220104493A1-20220407-C00226
3. The compound of formula (I) according to claim 2, wherein R1 and R2 are independently selected from the group consisting of hydrogen and C1-C6alkyl.
4. The compound of formula (I) according to claim 2, wherein R1 and R2 are hydrogen.
5. The compound of formula (I) according to claim 2, wherein each R1a and R2b are independently selected from the group consisting of hydrogen, C1-C6alkyl, —OH and —NH2.
6. The compound of formula (I) according to claim 2, wherein each R1a and R2b are hydrogen.
7. The compound of formula (I) according to claim 2, wherein m is 0, 1 or 2.
8. The compound of formula (I) according to claim 2, wherein R3, R3a, R4 and R5 are independently selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl and C1-C6fluoroalkyl.
9. The compound of formula (I) according to claim 2, wherein R3, R3a, R4 and R5 are hydrogen.
10. The compound of formula (I) according to claim 2, wherein A is selected from the group consisting of formula A-I to A-XXXII below
Figure US20220104493A1-20220407-C00227
Figure US20220104493A1-20220407-C00228
Figure US20220104493A1-20220407-C00229
Figure US20220104493A1-20220407-C00230
wherein the jagged line defines the point of attachment to a compound of formula (I);
R8a is selected from the group consisting of hydrogen, C1-C6alkyl and C1-C6haloalkyl;
each R8b, R8c and R8d are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, —NH2, —S(O)rR15, —C(O)OR10, —C(O)R15, —C(O)NR16R17, —S(O)2NR16R17, C1-C6alkyl and C1-C6haloalkyl;
and R10, R15, R16, R17 and r are as defined in claim 1.
11. The compound of formula (I) according to claim 2, wherein A is selected from the group consisting of formula A-I to A-III below
Figure US20220104493A1-20220407-C00231
wherein the jagged line defines the point of attachment to a compound of formula (I);
each R8b is independently selected from the group consisting of hydrogen, halogen, cyano, —NH2, —C(O)NR16R17, C1-C6alkyl and C1-C6haloalkyl;
and R16 and R17 are as defined in claim 1.
12. The compound of formula (I) according to claim 2, wherein A is selected from the group consisting of formula A-Ia to A-Xa below
Figure US20220104493A1-20220407-C00232
13. The compound of formula (I) according to claim 2, wherein Z is selected from the group consisting of —C(O)OR10, —C(O)NHS(O)2R12, —OS(O)2OR10, —S(O)2OR10, and —P(O)(R13)(OR10).
14. The compound according to claim 2, wherein Z is —C(O)OH or —S(O)2OH.
15. The compound according to claim 2, wherein n is 0.
16. (canceled)
17. The method of claim 1, wherein the applying is pre-harvest desiccation in crops.
18. An agrochemical composition comprising a herbicidally effective amount of a compound of formula (I) as defined in claim 1 and an agrochemically-acceptable diluent or carrier.
19. A method of controlling unwanted plant growth, comprising applying a compound of formula (I) as defined in claim 2, to the unwanted plants or to the locus thereof.
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